ORIGINAL RESEARCH published: 01 February 2022 doi: 10.3389/fmed.2022.823900 Immigrant IBD Patients in Spain Are Edited by: Levinus Albert Dieleman, University of Alberta, Canada Younger, Have More Extraintestinal Reviewed by: Nazri Mustaffa, Manifestations and Use More Universiti Sains Malaysia (USM), Malaysia Biologics Than Native Patients Vivian Huang, University of Toronto, Canada Ana Gutiérrez 1,2,3*, Pedro Zapater 2,3,4,5 , Elena Ricart 3,6 , María González-Vivó 7 , *Correspondence: Jordi Gordillo 8 , David Olivares 9 , Isabel Vera 10 , Míriam Mañosa 3,11 , Javier P. Gisbert 3,12 , Ana Gutiérrez Mariam Aguas 3,13 , Eugenia Sánchez-Rodríguez 14 , Maia Bosca-Watts 15 , Viviana Laredo 16 , gutierrez_anacas@gva.es Blau Camps 17 , Ignacio Marín-Jiménez 18,19 , Yamile Zabana 3,20 , Rubén Francés María Dolores Martín-Arranz 21 , Roser Muñoz 1 , Mercè Navarro 22 , Eva Sierra 23 , rfrances@umh.es Lucía Madero 24 , Milagros Vela 25 , José Lázaro Pérez-Calle 26 , Empar Sainz 27 , Xavier Calvet 3,28 , Lara Arias 29 , Victor Morales 30 , Fernando Bermejo 31,32 , Specialty section: Luis Fernández-Salazar 33 , Manuel Van Domselaar 34 , Luisa De Castro 35 , This article was submitted to Cristina Rodríguez 36 , Carmen Muñoz-Villafranca 37 , Rufo Lorente 38 , Montserrat Rivero 39 , Gastroenterology, Eva Iglesias 40,41 , Belén Herreros 42 , David Busquets 43 , Joan Riera 44 , a section of the journal María Pilar Martínez-Montiel 45 , Marta Roldón 46 , Oscar Roncero 47 , Esther Hinojosa 48 , Frontiers in Medicine Mónica Sierra 49 , Jesús Barrio 50 , Ruth De Francisco 51 , José Huguet 52 , Olga Merino 53 , Received: 28 November 2021 Daniel Carpio 54 , Daniel Ginard 55 , Fernando Muñoz 56 , Marta Piqueras 57 , Pedro Almela 58 , Accepted: 12 January 2022 Federico Argüelles-Arias 59 , Guillermo Alcaín 60 , Luis Bujanda 3,61,62 , Noemí Manceñido 63 , Published: 01 February 2022 Alfredo J. Lucendo 3,64 , Pilar Varela 65 , Iago Rodríguez-Lago 66,67 , Laura Ramos 68 , Citation: Laura Sempere 1,2 , Eva Sesé 69 , Manuel Barreiro-de Acosta 70 , Eugeni Domènech 3,11 and Gutiérrez A, Zapater P, Ricart E, Rubén Francés 2,3,71,72* on behalf of the ENEIDA Project of GETECCU González-Vivó M, Gordillo J, 1 Olivares D, Vera I, Mañosa M, Servicio Medicina Digestiva, Hospital General Universitario Alicante, Alicante, Spain, 2 IIS Isabial, Hospital General Gisbert JP, Aguas M, Universitario Alicante, Alicante, Spain, 3 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas Sánchez-Rodríguez E, (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain, 4 Unidad Farmacología Clínica, Hospital General Universitario Bosca-Watts M, Laredo V, Camps B, Alicante, Alicante, Spain, 5 Instituto IDIBE, Universidad Miguel Hernández, San Juan de Alicante, Spain, 6 Servicio de Marín-Jiménez I, Zabana Y, Medicina Digestiva Hospital Clínic, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 7 Martín-Arranz MD, Muñoz R, Servicio Medicina Digestiva, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain, 8 Navarro M, Sierra E, Madero L, Servicio Patología Digestiva, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain, 9 Servicio Medicina Digestiva, Hospital Vela M, Pérez-Calle JL, Sainz E, Universitario Clínico San Carlos, Madrid, Spain, 10 Servicio Aparato Digestivo, Hospital Universitario Puerta de Hierro, Madrid, Calvet X, Arias L, Morales V, Spain, 11 Servicio Aparato Digestivo, Hospital Universitari Germans Trias I Pujol, Badalona, Spain, 12 Servicio de Aparato Bermejo F, Fernández-Salazar L, Van Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma Domselaar M, De Castro L, de Madrid (UAM), Madrid, Spain, 13 Servicio Medicina Digestiva, Hospital Universitario La Fé, Valencia, Spain, 14 Servicio Rodríguez C, Muñoz-Villafranca C, Medicina Digestiva, Hospital Universitario Ramón y Cajal, Madrid, Spain, 15 Servicio Medicina Digestiva, Hospital Clínico Lorente R, Rivero M, Iglesias E, Universitario de Valencia, Valencia, Spain, 16 Servicio Medicina Digestiva, Hospital Clinico Universitario Lozano Blesa, Herreros B, Busquets D, Riera J, Zaragoza, Spain, 17 Servicio Medicina Digestiva, Hospital Universitario de Bellvitge, Barcelona, Spain, 18 Servicio Medicina Martínez-Montiel MP, Roldón M, Digestiva, Hospital Gregorio Marañón, Madrid, Spain, 19 Gastroenterology Department, Instituto de Investigación Biomédica Roncero O, Hinojosa E, Sierra M, Gregorio Marañón IiSGM, Madrid, Spain, 20 Servicio Medicina Digestiva, Hospital Universitari Mútua Terrassa, Terrassa, Barrio J, De Francisco R, Huguet J, Spain, 21 Servicio Medicina Digestiva, Hospital La Paz, Madrid, Spain, 22 Servicio Medicina Digestiva, Hospital de Sant Joan Merino O, Carpio D, Ginard D, Despí Moisès Broggi, Barcelona, Spain, 23 Servicio Medicina Digestiva, Hospital Universitario Miguel Servert, Zaragoza, Muñoz F, Piqueras M, Almela P, Spain, 24 Servicio Medicina Digestiva, Hospital General Universitario de Elche, Elche, Spain, 25 Servicio Medicina Digestiva, Argüelles-Arias F, Alcaín G, Bujanda L, Hospital Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain, 26 Servicio Medicina Digestiva, Hospital Manceñido N, Lucendo AJ, Varela P, Universitario Fundación de Alcorcón, Madrid, Spain, 27 Servicio Medicina Digestiva, Hospital Sant Joan de Déu - Althaia, Rodríguez-Lago I, Ramos L, Manresa, Spain, 28 Unitat Malalties Digestives, Hospital de Sabadell, Institut Universitari Parc Tauli, Universidad Autónoma de Sempere L, Sesé E, Barreiro-de Barcelona (UAB), Barcelona, Spain, 29 Servicio Medicina Digestiva, Hospital Universitario de Burgos, Burgos, Spain, 30 Acosta M, Domènech E and Servicio Medicina Digestiva, Hospital General de Granollers, Barcelona, Spain, 31 Servicio Medicina Digestiva, Hospital de Francés R (2022) Immigrant IBD Fuenlabrada, Fuenlabrada, Spain, 32 IIS Hospital La Paz IdiPaz-Madrid, Madrid, Spain, 33 Servicio Medicina Digestiva, Patients in Spain Are Younger, Have Hospital Clínico de Valladolid, Madrid, Spain, 34 Servicio Medicina Digestiva, Hospital de Torrejón de Ardoz, Madrid, Spain, 35 More Extraintestinal Manifestations Department of Gastroenterology, Xerencia Xestion Integrada de Vigo- SERGAS. IIS Galicia Sur. SERGAS-UVIG, Vigo, and Use More Biologics Than Native Spain, 36 Servicio Medicina Digestiva, Complejo Hospitalario de Navarra, Pamplona, Spain, 37 Servicio Medicina Digestiva, Patients. Front. Med. 9:823900. Hospital Universitario de Basurto, Bilbao, Spain, 38 Servicio Medicina Digestiva, Hospital General Ciudad Real, Ciudad Real, doi: 10.3389/fmed.2022.823900 Spain, 39 Servicio Medicina Digestiva, Hospital Universitario Marqués de Valdecilla and IDIVAL, Santander, Spain, Frontiers in Medicine | www.frontiersin.org 1 February 2022 | Volume 9 | Article 823900 Gutiérrez et al. Immigrant IBD Population in Spain 40 Servicio Medicina Digestiva, Hospital Universitario Reina Sofía, Córdoba, Spain, 41 Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain, 42 Servicio Medicina Digestiva, Hospital Marina Baixa, Villajoyosa, Spain, 43 Servicio Medicina Digestiva, Hospital de Girona Dr. Trueta/ICO, Girona, Spain, 44 Servicio Medicina Digestiva, Hospital Universitario Son LLàtzer, Palma de Mallorca, Spain, 45 Servicio Medicina Digestiva, Hospital 12 de Octubre, Madrid, Spain, 46 Servicio Cirugía General y del Aparato Digestivo, Hospital San Jorge, Huesca, Spain, 47 Servicio Medicina Digestiva, Hospital General La Mancha Centro, Ciudad Real, Spain, 48 Servicio Medicina Digestiva, Hospital de Manises, Valencia, Spain, 49 Servicio Medicina Digestiva, Complejo Asistencial Universitario de León, León, Spain, 50 Hospital Universitario Rio Hortega, Valladolid, Spain, 51 Hospital Universitario Central de Asturias and ISPA, Oviedo, Spain, 52 Consorcio Hospital General Universitario de Valencia, Valencia, Spain, 53 Servicio Medicina Digestiva, Hospital de Cruces, Bilbao, Spain, 54 Complejo Hospitalario Universitario Pontevedra, Pontevedra, Spain, 55 Servicio Medicina Digestiva, Hospital Universitario Son Espases, Palma de Mallorca, Spain, 56 Servicio Medicina Digestiva, Hospital Clínico Universitario Salamanca, Salamanca, Spain, 57 Servicio Medicina Digestiva, Consorci Sanitari Terrasa, Barcelona, Spain, 58 Servicio Medicina Digestiva, Hospital General Universitario Castellón, Castellón de la Plana, Spain, 59 Servicio Medicina Digestiva, Hospital Universitario Virgen Macarena, Sevilla, Spain, 60 Servicio Medicina Digestiva, Hospital Clínico Virgen de la Victoria, Málaga, Spain, 61 Servicio Medicina Digestiva, Hospital Universitario Donostia, San Sebastián, Spain, 62 Instituto Biodonostia, Universidad Pais Vasco, San Sebastián, Spain, 63 Servicio Medicina Digestiva, Hospital Infanta Sofía, Madrid, Spain, 64 Servicio Medicina Digestiva, Hospital General Tomelloso, Ciudad Real, Spain, 65 Servicio Medicina Digestiva, Hospital Cabueñes, Gijón, Spain, 66 Servicio de Aparato Digestivo, Hospital Universitario de Galdakao, IIS Biocruces, Galdakao, Spain, 67 Facultad de Medicina, University of Deusto, Bilbao, Spain, 68 Servicio Medicina Digestiva, Hospital Universitario La Laguna, Santa Cruz Tenerife, Spain, 69 Servicio Medicina Digestiva, Hospital Arnau de Vilanova, Lleida, Spain, 70 Servicio Aparato Digestivo, Hospital Universitario Santiago, Santiago de Compostela, Spain, 71 Hepatic and Intestinal Immunobiology Group, Dpto. Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain, 72 Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain Background: Previous studies comparing immigrant ethnic groups and native patients with IBD have yielded clinical and phenotypic differences. To date, no study has focused on the immigrant IBD population in Spain. Methods: Prospective, observational, multicenter study comparing cohorts of IBD patients from ENEIDA-registry who were born outside Spain with a cohort of native patients. Results: We included 13,524 patients (1,864 immigrant and 11,660 native). The immigrants were younger (45 ± 12 vs. 54 ± 16 years, p < 0.001), had been diagnosed younger (31 ± 12 vs. 36 ± 15 years, p < 0.001), and had a shorter disease duration (14 ± 7 vs. 18 ± 8 years, p < 0.001) than native patients. Family history of IBD (9 vs. 14%, p < 0.001) and smoking (30 vs. 40%, p < 0.001) were more frequent among native patients. The most prevalent ethnic groups among immigrants were Caucasian (41.5%), followed by Latin American (30.8%), Arab (18.3%), and Asian (6.7%). Extraintestinal manifestations, mainly musculoskeletal affections, were more frequent in immigrants (19 vs. 11%, p < 0.001). Use of biologics, mainly anti-TNF, was greater in immigrants (36 vs. 29%, p < 0.001). The risk of having extraintestinal manifestations [OR: 2.23 (1.92–2.58, p < 0.001)] and using biologics [OR: 1.13 (1.0–1.26, p = 0.042)] was independently associated with immigrant status in the multivariate analyses. Conclusions: Compared with native-born patients, first-generation-immigrant IBD patients in Spain were younger at disease onset and showed an increased risk of having extraintestinal manifestations and using biologics. Our study suggests a featured phenotype of immigrant IBD patients in Spain, and constitutes a new landmark in the epidemiological characterization of immigrant IBD populations in Southern Europe. Keywords: immigrant, phenotype, biologics, inflammatory bowel disease, Crohn’s disease, ulcerative colitis HIGHLIGHTS - Studies evaluating phenotypic characteristics of immigrant IBD populations show specific features that are not always What is known? reproduced in native patients. Frontiers in Medicine | www.frontiersin.org 2 February 2022 | Volume 9 | Article 823900 Gutiérrez et al. Immigrant IBD Population in Spain - Few studies have evaluated the characteristics of immigrant which has a population of 47 million people and more than 5 IBD patients in Southern Europe and, to date, none has million foreign residents (www.ine.es/en). focused on the immigrant IBD population in Spain. This study aimed to explore the characteristics of immigrant What is new here? IBD patients in Spain compared with native IBD patients, focusing on potential differences in age of disease onset, IBD - The main ethnic groups of immigrant IBD patients in Spain phenotype, and therapeutic requirements. are Caucasian, Latin American and Arab. - Immigrant IBD patients in Spain are younger and have more extraintestinal manifestations than native-born METHODS patients. Accordingly, the use of biologics is more frequent among immigrants. Study Design This was an observational, prospective, multicenter, nationwide - The study represents a new landmark in the epidemiologic study carried out with data from ENEIDA project (16). ENEIDA characterization of immigrant patients with IBD in is a large, prospectively maintained nationwide registry of Southern Europe. IBD patients in Spain. It was set up in 2006 by the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis INTRODUCTION (GETECCU) and undergoes continuous external monitoring to ensure completeness and consistency of the entered data. At the Inflammatory bowel disease (IBD) is a term that covers time of the study, the database contained data from over 69,000 Crohn’s disease (CD) and ulcerative colitis (UC), which are patients from ∼100 actively participating centers. chronic, progressive and disabling diseases characterized by cycles of remission and relapse. Though the cause of IBD is Study Population and Data Collection not yet fully understood, its pathogenesis has been linked to The immigrant cohort of our study comprised all adult IBD complex interactions between genetic, epithelial, immune, patients born outside of Spain (first-generation immigrants) microbial and environmental factors (1, 2). Although more and included in the ENEIDA registry. Any conflicting data than 240 IBD-associated risk variants have been identified regarding date of migration to Spain, country of birth, ethnicity, to date by large genome-wide association studies (3), genetic or date of IBD diagnosis were checked against patient’s clinical background seems only to partially explain susceptibility to records by ENEIDA project investigators. The second cohort the disease and in most cases, environmental risk factors was a large, randomly selected sample of adult native IBD are also involved in disease onset and progression (4, 5). patients included in the ENEIDA database. Native IBD patients However, studies focusing on causative environmental were born in Spain and were all Caucasians. Inclusion criteria factors are challenging and have produced conflicting were diagnosis with UC, CD or IBD unclassified (IBDU) based results (6). on the accepted criteria of the European Crohn’s and Colitis The epidemiology of IBD has changed over time and Organization (ECCO) (17); diagnosis before 2015, to ensure is influenced by geographical variations, suggesting that follow-up of at least 5 years; and age 16 years or older. The environmental factors play a role in modifying its expression ENEIDA project was approved by research ethics committees in (7). In fact, newer epidemiologic studies define IBD as a all participating centers and the GETECCU scientific committee. global disease, suggesting that its incidence either continues All patients gave written informed consent before being enrolled to grow steadily or remains stable in western countries while in the ENEIDA registry. rapidly increasing in developing countries (8), possibly owing to their increasingly westernized lifestyle (9). Moreover, Patient Demographics, Disease Phenotype studies carried out among migrants show that they tend to and Disease Course acquire the disease incidence of their adopted country rather We collected the following demographic characteristics of the than the country of origin, reflecting the importance of the included patients: age, sex, smoking status, ethnicity, country of environmental risk factors such as lifestyle, pollution and birth, date of migration to Spain, date of IBD diagnosis, duration diet (10–12). of the disease, and family history of IBD. The ethnic groups were Migration has increased in the past decades together with classified as Caucasian, Latin American, Arab, Asian, African, globalization. Several studies have been conducted in large, well- Roma, and Jewish. Using the United Nations Standard Country defined migrant groups such as Mexicans living in the USA and or Area Codes for Statistical Use, M49 standard (https://unstats. people from India living in Europe, the USA or the Middle un.org/unsd/methodology/m49/) we categorized the birthplace East (13). A recent review on the epidemiology of IBD in of immigrants into the following geographical regions: Northern migrant racial and ethnic groups revealed differences in disease Africa, Central Africa, South America, Northern America, incidence, prevalence and phenotypes between immigrants and Central America, Caribbean, Eastern Europe, Western Europe, native patients in individual studies (14). However, few studies Southern Europe, Northern Europe, Southern Asia, Western of this kind have analyzed European populations. Although there Asia, Eastern Asia, Southeast Asia, and Oceania. is evidence showing an increased risk of IBD in Spanish people We used the Montreal classification of IBD to classify disease who have migrated to Western Europe (15), to date no study has phenotypes according to extent of UC and location and behavior explored the characteristics of immigrant IBD patients in Spain, of CD (18). Surgical procedures were defined as interventions Frontiers in Medicine | www.frontiersin.org 3 February 2022 | Volume 9 | Article 823900 Gutiérrez et al. Immigrant IBD Population in Spain related directly to IBD or its complications, including both TABLE 1 | Demographic and clinical characteristics of the immigrant and abdominal and perianal surgeries. Pharmacological treatment native-born IBD population in Spain. collected included type and time to initiation of first biologic Immigrants Natives P-value agent and use of immunomodulator agents (methotrexate, (n = 1,864) (n = 11,660) azathioprine, or 6-mercaptopurine). Gender, female (n,%) 936 (50.2) 5444 (46.7) 0.005 Statistical Analysis Mean current age (SD) 45.3 (12.6) 54.5 (16.0) <0.001 Continuous variables are reported as means with standard Mean age at IBD diagnosis 31.2 (12.0) 36.5 (15.6) <0.001 deviations and categorical variables as absolute and relative Mean duration of disease (SD) 14.0 (7.2) 18.0 (8.7) <0.001 frequencies. Differences between immigrant and native Smoking habit populations were analyzed using the two-tailed t test and no (n,%) 1181 (69.3) 6952 (59.5) <0.001 Mann-Whitney U test for normally and non-normally yes (n,%) 296 (17.4) 2227 (19.1) distributed quantitative variables, respectively. We analyzed Ex (n,%) 227 (13.3) 2508 (21.5) categorical variables using the Chi-square test. Univariate and Crohn’s disease (n,%) 777 (41.8) 4755 (40.8) 0.068 multivariate logistic regression analyses were performed to Ulcerative colitis (n,%) 1029 (55.4) 6665 (57.2) assess potential risk factors for the development of EIMs, use Unclassified IBD (n,%) 52 (2.8) 240 (2.1) of biologics, surgery, and death. Only significant variables from Crohn’s age at diagnosis the univariable analysis were entered into the regression model. A1 (<16y) (n,%) 67 (8.6) 275 (5.8) <0.001 Estimations of crude odds ratios (ORs) and their 95% confidence A2 (16-40y) (n,%) 586 (75.3) 3223 (67.8) intervals (CIs) were estimated using logistic regression analysis. A3 (>40y) (n,%) 125 (16.1) 1257 (26.4) Timeframe between study entry and surgery or initiation of Crohn’s location treatment with biologics was analyzed using Kaplan-Meier L1 (ileal) (n,%) 154 (28.5) 1025 (28.4) 0.368 life-table analysis, as precise dates were known. Log-rank test L2 (colonic) (n,%) 112 (20.7) 640 (17.7) was used to compare survival curves. All reported P-values are L3 (ileocolonic) (n,%) 233 (43.1) 1636 (45.3) 2-sided, and P-values lower than 0.05 are considered to indicate L4 (upper GI) (n,%) 42 (7.8) 308 (8.5) statistical significance. All analyses were carried out in the R Crohn’s behavior software environment (Core Team 2014, Vienna, Austria). B1 (inflammatory) 482 (63.9) 2744 (57.7) 0.002 B2 (stricturing) (n,%) 144 (19.1) 1158 (24.4) RESULTS B3 (perforating) (n,%) 128 (17.0) 853 (17.9) Demographic Characteristics Perianal perforating (n;%) 242 (13.7) 1776 (15.4) 0.069 Ulcerative colitis extent A total of 13,524 patients were included in this study, 1,864 of whom were immigrants born outside Spain. The Proctitis (n,%) 186 (29.7) 1478 (31.9) 0.031 comparative cohort included 11,660 Caucasian IBD patients Left sided colitis (n,%) 357 (57.0) 2689 (58.1) born in Spain. Table 1 summarizes the main demographic Extensive colitis (n,%) 83 (13.3) 459 (9.9) characteristics of immigrants and native patients. Median age Extraintestinal manifestations (n;%) 318 (18.9) 1275 (10.9) <0.001 of the immigrant group at the time of arrival in Spain Family history of IBD (n,%) 155 (9.4) 1676 (14.3) <0.001 was 26 years (range 0–78 years). No differences in IBD diagnosis and sex were observed between the two groups comprising all IBD patients, but more native than immigrant patients diagnosed with UC were men. Immigrant IBD patients Figure 1A shows the distribution by ethnicity of the were younger at inclusion, were diagnosed earlier in life, immigrant cohort. The most prevalent ethnic group was and had a shorter disease duration than native patients. Caucasian (41.5%, 771), followed by Latin American (30.8%, 572) These differences persisted when CD and UC patients were and Arab (18.3%, 341), whereas Asians represented a minority analyzed separately (Supplementary Tables 1, 2). Immigrants (6.7%, 125). Supplementary Table 5 shows the characteristics aged younger than 15 years on arrival in Spain were significantly of immigrant patients by ethnicity. UC diagnosis was more younger at disease onset than those who migrated after common among Latin American and Asian IBD patients age 15 (23.24 ± 11.34 vs. 32.12 ± 11.28, p < 0.001, compared with Caucasians and Arabs. The distribution of Supplementary Table 3). Family history of IBD and smoking the immigrant population by geographical area of birth is (present or past) were more frequent in native patients than represented in Figure 1B. South America was the most frequent in immigrants (14.3 vs. 9.4%, p = 0.001; and 40.6 vs. 28%, birthplace, followed by North Africa and Eastern Europe. p = 0.001, respectively). No differences were found regarding the frequency of appendectomies between the two groups. Disease Phenotype Seventy-one percent of immigrant patients were diagnosed Phenotypic IBD characteristics of both cohorts are displayed in with IBD in Spain. Supplementary Table 4 compares the main Table 1. Disease location in CD patients did not differ between demographic characteristics of immigrants diagnosed in Spain vs. the two groups. Regarding the age of disease onset, the number outside Spain. of patients diagnosed under 16 years (A1) was significantly Frontiers in Medicine | www.frontiersin.org 4 February 2022 | Volume 9 | Article 823900 Gutiérrez et al. Immigrant IBD Population in Spain FIGURE 1 | (A) Distribution of immigrant population by ethnicity. (B) Distribution of immigrant population by geographical area of birth according to OMS Standard Country or Area Codes for Statistical Use, M49 standard. higher among immigrant compared with native CD patients. history of IBD was unrelated (Figure 2A). These factors In contrast, the number of patients diagnosed over 40 years remained independently associated with an increased risk (A3) was significantly higher in the native group. Stricturing of EIMs when the patients were divided into CD and UC behavior was more frequent among native CD patients, although patients (Figures 2B,C). Supplementary Table 7 describes the the multivariate analysis found no independent association complete univariate and multivariate analyses for EIMs in between stricturing behavior and being native. Similarly, IBD patients. stricturing behavior was not independently associated with smoking but was associated with longer disease duration Therapeutic Requirements and Disease (Supplementary Table 6). We found no significant difference Course in the prevalence of perianal disease between the two groups. Table 3 summarizes the different medical treatments and surgical In UC patients, the distribution of ulcerative proctitis, left procedures in both groups of patients. Endoscopic treatment sided UC and extensive UC was similar in immigrant and was more frequent among native patients, while no significant native patients. differences between groups were present regarding the use of EIMs were significantly more frequent among immigrant immunosuppressants (mainly thiopurines). In contrast, the use compared with native IBD patients (Table 1). The list of of biologics was significantly more frequent in the subgroup EIMs is detailed in Table 2. Musculoskeletal affections of immigrants compared with native patients. Of the different were the most frequent EIM among patients in both biologics, anti-TNF was the most frequently prescribed in both groups. Primary sclerosing cholangitis was more frequent subgroups. Younger age, longer duration of disease, family in immigrant compared with native patients only in the history of IBD and being a immigrant were also independently cohort of UC patients. In the multivariate analysis, the associated with the use of biological therapy in the complete risk of suffering EIMs among the complete series of IBD series of IBD patients in the multivariate analysis (Figure 3A). patients was independently associated with female sex, longer While all these variables remained independently associated with duration of disease and being an immigrant, while family the use of biologics in the cohort of CD patients, family history Frontiers in Medicine | www.frontiersin.org 5 February 2022 | Volume 9 | Article 823900 Gutiérrez et al. Immigrant IBD Population in Spain FIGURE 2 | Forest plots representing the odds ratio for presenting with EIMs in the multivariate analysis for the global (A), CD (B), and UC (C) cohorts of patients. CD, Crohn’s disease; UC, ulcerative colitis. TABLE 2 | Extraintestinal manifestations in the immigrant and native-born IBD TABLE 3 | Medical treatments and surgical procedures in the immigrant and population in Spain. native-born IBD population in Spain. Immigrants Natives p-value Immigrants Natives p-value N (%) (n = 395) (n = 1,608) N (%) Peripheral arthritis 164 (42.3) 582 (25.3) <0.001 Endoscopic treatment 24/1517 (1.6) 425/10663 (3.9) <0.001 Ankylosing spondylitis 52 (14.2) 158 (6.1) <0.001 Immunosuppresants 1006/1835 (54.8) 6126/11651 (52.6) 0.082 Isolated sacroiliitis 29 (13.9) 166 (18.2) 0.176 Biologics 643/1766 (36.4) 3469/11651 (29.8) <0.001 Erythema nodosum 40 (17.6) 221 (10.5) 0.002 AntiTNF 637 (34.2) 3405 (29.2) 0.038 Pyoderma gangrenosum 11 (6.0) 67 (3.2) 0.078 Vedolizumab 2 (0.1) 41 (2.5) Aphtous stomatitis 31 (8.8) 156 (6.0) 0.005 Ustekinumab - 19 (0.16) Uveitis 25 (12.2) 76 (3.8) <0.001 Others 2 (0.1) 4 (0.03) Episcleritis 6 (3.5) 64 (3.2) 1.000 IBD-related surgery 389/1763 (22.1) 2742/11651 (23.5) 0.184 Primary sclerosing cholangitis 21 (5.9) 41 (1.6) <0.001 Abdominal surgery for CD* 276 (29.4) 2253 (34.5) 0.002 Thrombosis 16 (4.5) 77 (3.0) 0.167 Total proctocolectomy for UC** 37 (3.5) 240 (3.4) 1 Perianal surgery 154 (8.3) 1372 (11.8) 0.184 Percentages are calculated based on patients with available data. *Percentage calculated on CD patients. **Percentage calculated on UC patients. and being a immigrant were not independently associated with an increased risk of using biologics in the multivariate analysis among UC patients (Figures 3B,C). Supplementary Table 8 CD and UC cohorts of patients were analyzed separately describes the univariate and multivariate analyses for the use (Figures 4B,C). Supplementary Table 9 shows the univariate of biologics in IBD patients. Time to first biologic drug during and multivariate analyses for the risk for surgical treatment in follow-up was significantly earlier in immigrant vs. native the series of IBD patients. Time to surgery during follow-up was patients according to the performed survival analysis of the time not different between native vs. immigrant patients according to first biologic drug (Figure 3D). to the performed survival analysis of the time to intestinal No significant differences were found in the frequency surgery (Figure 4D). of IBD-related abdominal and perianal surgeries between all Loss to follow-up was more frequent among immigrant IBD immigrant and native IBD patients, or in the frequency of patients (n = 265, 14.6 vs. n = 1,216, 10.4%; p = 0.001). Mean proctocolectomy between native and immigrant UC patients. follow-up was 5.6 ± 6.2 years in the immigrant subgroup and However, abdominal surgery was significantly more frequent 6.1 ± 4.5 years in the subgroup of native patients (p = 0.016). among native vs. immigrant CD patients. The risk of surgical Significantly more native than immigrant patients died during treatment was not associated with immigrant status. Female the study period (2.6%, n = 300 vs. 0.9%, n = 17; p < 0.01). sex, longer duration of disease, and family history of IBD The cause of death was available for 179 natives (59.6%) and 3 were associated with this parameter in the global cohort of immigrants (17.6%). The most frequent causes of death in native all IBD patients (Figure 4A), although only female sex and patients were neoplasm (n = 97, 54.2%) and infection (n = 30, longer duration of disease remained independently associated, 16.7%). The three recorded causes of death among immigrants with a significantly decreased risk of surgical treatment, when were neoplasm (n = 1), infection (n = 1), and others (n = 1). Frontiers in Medicine | www.frontiersin.org 6 February 2022 | Volume 9 | Article 823900 Gutiérrez et al. Immigrant IBD Population in Spain FIGURE 3 | Forest plots representing the odds ratio for using biologics in the multivariate analysis for the global (A), CD (B), and UC (C) cohorts of patients. (D) Survival analysis of the time to first biologic drug in immigrant vs. native patients. CD, Crohn’s disease; UC, ulcerative colitis. Supplementary Table 10 shows the recorded causes of death in To explain the observed difference in age at onset, we may both subgroups. speculate on the relevance of the so called exposome (22), or the accumulation of environmental exposures, including several disease triggering factors such as microbiota dysbiosis, smoking DISCUSSION and use of antibiotics. A study by Damas et al. (23) found earlier IBD onset among young Cuban migrants to America compared We present the first study exploring the characteristics of with previous migratory cohorts, suggesting a more intensive first-generation immigrant IBD population in Spain, extracted exposure to environmental triggering factors in the more recent from the vast ENEIDA nationwide registry of GETECCU. The arrivals. We also found that patients who were younger than 15 immigrant cohort (>1,800 patients) was younger at disease onset years on arrival in Spain were significantly younger at disease and showed an increased risk of having EIMs and using biologics onset than those who migrated after 15. This fact highlights the compared with the native cohort (>11,000 patients). Our results relevance of early-life exposure to environmental risk factors add to the scarce epidemiologic data characterizing immigrant for disease. Age of migration is an important factor in IBD IBD patients in Southern Europe, and suggest that immigrant development and phenotype, with younger ages being more IBD patients in Spain may have a distinct IBD phenotype. affected in terms of incidence. In line with observations from The population of first-generation immigrants diagnosed with our study, South Asians younger than 5 years-old at migration to IBD and living in Spain is mainly Caucasian and Latin American, US, or descendants who were already born in US, were younger though a large proportion of patients are of Arab ethnicity. Asian at IBD onset than those who were older than 5 years-old at patients make up a far smaller section of the population, unlike in migration (24). series evaluated in other studies—mainly from the USA and the UC predominance over CD in IBD diagnosis has been UK—in which South Asians constitute the most prevalent ethnic described in certain ethnic groups such as South Asian and group (19–21). While those same studies found no differences Hispanic (25–27). Our study also found a higher proportion of in age at disease onset, we present data showing that the first- UC among Latin American and Asian patients compared with generation-immigrant IBD population in Spain is younger than other ethnicities. This finding is consistent with findings reported native patients at disease onset and has a shorter disease duration. of South Asians cohorts in the UK and North America, where Frontiers in Medicine | www.frontiersin.org 7 February 2022 | Volume 9 | Article 823900 Gutiérrez et al. Immigrant IBD Population in Spain FIGURE 4 | Forest plots representing the odds ratio of surgery in the multivariate analysis for the global (A), CD (B), and UC (C) cohorts of patients. (D) Survival analysis of the time to surgery in immigrant vs. native patients. CD, Crohn’s disease; UC, ulcerative colitis. the burden of UC is believed to be twice that of CD (19, 21, 24). with longer disease duration in the multivariate analysis. The Indeed, one meta-analysis showed that UC was more frequent longer disease history probably reflects the accumulation of among Hispanic vs. non-Hispanic Americans (28), and studies disease progression milestones. Similar results were obtained conducted in Mexico and South America have reported UC to in a multicenter study on African-American compared with be the predominant IBD subtype (29–32). Interestingly, other Caucasian patients (38). Although other studies showed no series have found that Hispanic patients are not only more likely differences in behavior between immigrant and host populations to have UC but are also less likely than the non-Hispanic white (20), one potential explanation for increased stricturing in our population to have a family history of IBD (33, 34). We also found native cohort may derive from the genetic perspective. The allele a lower frequency of family history of the disease among our frequency of various mutations within NOD2/ CARD15 may immigrant cohort, which suggests that the cause is more likely help to explain differences in ethnic risks (39). Indeed, NOD2 to be de novo or sporadic. This observation is in line with other variations are less frequent among African Americans (40), and reports of sporadic disease among non-Caucasian ethnic groups South Asian patients compared with Caucasian patients (41, 42). (35, 36). On the other hand, several studies have reported the A second explanation may relate to the higher prevalence of inverse association between smoking and presenting UC (37), smoking habit among native vs. immigrant patients. Smoking which may also help to explain the predominance of UC in Latin has been widely described as a risk factor for developing CD, American and Asian patients, who are less likely to smoke than determining disease location and the development of strictures Caucasian immigrants and native patients. or fistulae, and increasing the risk of surgery (43–45). Several studies have reported a more aggressive phenotype, The two main differences between first-generation immigrant defined as more frequently colonic and perianal, and with more and native IBD populations in Spain were the increased risk of penetrating and stricturing behavior, in South Asian migrants EIMs and use of biologics among immigrants. Previous studies (19, 20, 24). We did not observe differences in either CD on immigrant populations have not reported these findings location or UC extent in our study, possibly because Asian (19, 21, 24). In fact, a lower rate of EIMs has previously been patients represented only a small part of the immigrant series. described in Asian patients (46, 47). It is possible that we found We did find more frequent stricturing behavior among native vs. the opposite association because our cohort contained relatively immigrant CD patients, although stricturing was only associated few Asian patients, and indeed, our sub-analysis of the different Frontiers in Medicine | www.frontiersin.org 8 February 2022 | Volume 9 | Article 823900 Gutiérrez et al. Immigrant IBD Population in Spain ethnic groups showed increased rates of EIMs in Caucasian, In summary, we present the first study exploring the Latin American and Arab patients, but not in Asian patients. characteristics of first-generation immigrants with IBD in Although the physiological mechanisms of EIM development Spain.Immigrant patients were younger at disease onset and are poorly understood, several risks factors have been described, showed an increased risk of having EIMs and using biologics including longer disease duration, colonic CD, and female sex compared with native patients. These factors could constitute (48, 49). In our study, longer disease duration, female sex and features of an IBD phenotype for the immigrant population immigrant status were risk factors independently associated in Spain. Our study represents a new landmark in the with EIM development. Increased risk of EIMs can therefore epidemiologic characterization of IBD immigrant patients in be considered a component of the IBD phenotype in our Southern Europe. immigrant population. The use of biologics, meanwhile, was independently associated DATA AVAILABILITY STATEMENT with longer disease duration, younger age, and immigrant status. The increased frequency of EIMs among immigrants may explain The original contributions presented in the study are included this result, as anti-TNF is one of the most effective treatments in the article/Supplementary Material, further inquiries can be for managing EIMs in IBD (49, 50). In addition, younger disease directed to the corresponding authors. onset, as found in our immigrant cohort, is a poor prognostic factor (51), which may also help to explain the increased use ETHICS STATEMENT of biologics among our immigrant population. Interestingly, time to first biologic treatment during follow-up was shorter The studies involving human participants were reviewed in the immigrant population. Economic factors are thought to and approved by Ethics Committee from Hospital General be the primary driver of racial and ethnic disparities in health Universitario de Alicante. The patients/participants services utilization, including use of prescription medication provided their written informed consent to participate in (52). However, our results show that both native and immigrant this study. populations have full access to biologic therapies under the universal healthcare coverage provided by Spain’s public health AUTHOR CONTRIBUTIONS service, and low socioeconomic status is therefore unlikely to have contributed to differences in prescription patterns AG and RF: planning and/or conducting the study. AG, ER, in this study. On the other hand, clinical practice among MG-V, JG, DO, IV, MM, JPG, MA, ES-R, MB-W, VL, BC, IM-J, ENEIDA researchers is fairly uniform due to Spanish program YZ, MM-A, RM, MN, ESi, LM, MVe, JP-C, ESa, XC, LA, VM, of certification of quality of care at inflammatory bowel disease FB, LF-S, MVa, LD, CR, CM-V, RL, MRi, EI, BH, DB, JR, MM- units (53), which sets the standards of care in IBD all over the M, MRo, OR, EH, MS, JB, RD, JH, OM, DC, DG, FM, MP, PA, country. An alternative explanation is that immigrant patients FA-A, GA, LB, NM, AL, PV, IR-L, LR, LS, ESe, MB-d, and ED: may have a distinctive disease course. No differences in the collecting data. AG, RF, and PZ: interpreting data and drafting risk of IBD-related surgery were found between first-generation- of the manuscript. All authors contributed to the article and immigrant and native IBD populations in Spain. However, approved the submitted version. intestinal resection was more frequent among native CD patients. This may be related to the increased rate of stricturing behavior FUNDING and smoking habit, both described as risk factors for surgery in CD (44). The ENEIDA registry of GETECCU is supported by AbbVie, We must acknowledge that the retrospective study design and Galápagos, Janssen, Biogen, Takeda, Pfizer. AG is recipient of the lack of information regarding patient’s genetic background, a grant by Instituto de Salud Carlos III, Madrid, Spain (PI21/ dietary habits and socioeconomical status constitute limitations 1702). of the present study. On the other hand, the main strengths of our study were the large cohorts; the representation of SUPPLEMENTARY MATERIAL several ethnicities, including poorly studied groups such as Latin American or Arab immigrants; and the inclusion of patients The Supplementary Material for this article can be found diagnosed before 2015 to guarantee a follow-up period of at least online at: https://www.frontiersin.org/articles/10.3389/fmed. 5 years. 2022.823900/full#supplementary-material REFERENCES 3. Graham DB, Xavier RJ. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature. (2020) 1. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. 578:527–39. doi: 10.1038/s41586-020-2025-2 Ulcerative colitis. Lancet. (2017) 389:1756–70. doi: 10.1016/S0140-6736(16) 4. van der Sloot KWJ, Amini M, Peters V, Dijkstra G, Alizadeh BZ. 32126-2 Inflammatory bowel diseases: review of known environmental 2. Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn’s disease. 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(2007) research support and consulting fees from Abbvie, Adacyte, Almirall, Amgen, 26:1325–32. doi: 10.1111/j.1365-2036.2007.03524.x Dr. Falk, FAES Pharma, Ferring, Janssen, MSD, Otsuka, Pfizer, Shire, Takeda and 42. Pugazhendhi S, Amte A, Balamurugan R, Subramanian V, Ramakrishna BS. Tillots. XC has received grants for research from Abbvie, MSD, Vifor fees for Common NOD2 mutations are absent in patients with Crohn’s disease in advisory boards form Abbvie, MSD, Takeda, Pfizer, Janssen and VIFOR and has India. Indian J Gastroenterol. (2008) 27:201–3. given lectures for Abbvie, MSD, Janssen, Pfizer, Takeda, Shire and Allergan. FB 43. Picco MF, Bayless TM. Tobacco consumption and disease duration has served as a speaker, a consultant and advisory member for or has received are associated with fistulizing and stricturing behaviors in the research funding from MSD, Abbvie, Takeda, Janssen, Pfizer, Biogen, Amgen, first 8 years of Crohn’s disease. Am J Gastroenterol. (2003) Ferring, Faes Farma, Tillotts Pharma, Falk Pharma, Chiesi, Gebro Pharma, Vifor 98:363–8. doi: 10.1111/j.1572-0241.2003.07240.x Pharma. MM-M has served as speaker, consultant and advisory member for or 44. Reese GE, Nanidis T, Borysiewicz C, Yamamoto T, Orchard T, Tekkis has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Takeda, PP. The effect of smoking after surgery for Crohn’s disease: a meta- Janssen, Shire Pharmaceuticals and Otsuka Pharmaceutical. MR has served as analysis of observational studies. Int J Colorectal Dis. (2008) 23:1213– speaker, consultant or advisory member for MSD, Abbvie, Pfizer, Takeda, Janssen, 21. doi: 10.1007/s00384-008-0542-9 Ferring and Chiesi. MP has served as speaker or has received research funding 45. Quezada SM, Langenberg P, Cross RK. Cigarette smoking adversely affects from Abbvie, Takeda and Janssen. 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Distribution and manifestations or education funding from MSD, Abbvie, Kern Pharma, Ferring, FaesFarma, of inflammatory bowel disease in Asians, Hispanics, and African Shire Pharmaceuticals, Pfizer, Takeda, Janssen, Tillotts Pharma, and Otsuka Americans: a systematic review. AmJ Gastroenterol. (2009) Pharmaceutical. FA-A has served as speaker, consultant and advisory member for 104:2100–9. doi: 10.1038/ajg.2009.190 or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Takeda, 48. Hedin CRH, Vavricka SR, Stagg AJ, Schoepfer A, Raine T, Puig L, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Tillotts Pharma, Chiesi and et al. The pathogenesis of extraintestinal manifestations: implications for Dr. Falk. LR has served as a speaker, or has received education funding from IBD research, diagnosis, and therapy. J Crohns Colitis. (2019) 13:541– MSD, Abbvie, Adacyte, Takeda, Pfizer, Janssen and Ferring. MB-d has served as 54. doi: 10.1093/ecco-jcc/jjy191 a speaker, consultant and advisory member for or has received research funding 49. Harbord M, Annese V, Vavricka SR, Allez M. Barreiro-de Acosta M, Boberg from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gillead, Celgene, KM, et al. The first european evidence-based consensus on extra-intestinal Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, manifestations in inflammatory bowel disease. J Crohns Colitis. (2016) 10:239– Gebro Pharma, Adacyte and Vifor Pharma. ED has served as a speaker, or has 54. doi: 10.1093/ecco-jcc/jjv213 received research or education funding or advisory fees from AbbVie, Adacyte 50. Peyrin-Biroulet L, Van Assche G, Gomez-Ulloa D, Garcia-Alvarez L, Therapeutics, Biogen, Celltrion, Gilead, Janssen, Kern Pharma, MSD, Pfizer, Lara N, Black CM, et al. Systematic review of tumor necrosis factor Roche, Samsung, Takeda, Tillots, Thermofisher. RF has served as a speaker, or has antagonists in extraintestinal manifestations in inflammatory bowel disease. received research or education funding or advisory fees from AbbVie, Janssen, Clin Gastroenterol Hepatol. (2017) 15:25–36. doi: 10.1016/j.cgh.2016.06.025 Takeda, Adacyte Therapeutics, Sanofi, GlaxoSmithKline, Almirall. 51. Torres J, Caprioli F, Katsanos KH, Lobaton T, Micic D, Zeroncio M, et al. Predicting outcomes to optimize disease management in inflammatory bowel The remaining authors declare that the research was conducted in the absence of diseases. J Crohns Colitis. (2016) 10:1385–94. doi: 10.1093/ecco-jcc/jjw116 any commercial or financial relationships that could be construed as a potential 52. Wang J, Zuckerman IH, Miller NA, Shaya FT, Noel JM, Mullins CD. conflict of interest. Utilizing new prescription drugs: disparities among non-Hispanic whites, non-Hispanic blacks, and Hispanic whites. Health Serv Res. (2007) 42:1499– Publisher’s Note: All claims expressed in this article are solely those of the authors 519. doi: 10.1111/j.1475-6773.2006.00682.x and do not necessarily represent those of their affiliated organizations, or those of 53. Barreiro-de Acosta M, Gutierrez A, Zabana Y, Beltran B, Calvet X, Chaparro the publisher, the editors and the reviewers. Any product that may be evaluated in M, et al. Inflammatory bowel disease integral care units: Evaluation of this article, or claim that may be made by its manufacturer, is not guaranteed or a nationwide quality certification programme. The GETECCU experience. endorsed by the publisher. United European Gastroenterol J. (2021) 9:766–72. doi: 10.1002/ueg2.12105 Conflict of Interest: AG has served as speaker, consultant and advisory member Copyright © 2022 Gutiérrez, Zapater, Ricart, González-Vivó, Gordillo, Olivares, for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Vera, Mañosa, Gisbert, Aguas, Sánchez-Rodríguez, Bosca-Watts, Laredo, Camps, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Tillotts Pharma, Marín-Jiménez, Zabana, Martín-Arranz, Muñoz, Navarro, Sierra, Madero, Vela, Chiesi and Otsuka Pharmaceutical. ER has provided scientific advice/participated Pérez-Calle, Sainz, Calvet, Arias, Morales, Bermejo, Fernández-Salazar, Van in medical meetings/received research funding from/received payment for Domselaar, De Castro, Rodríguez, Muñoz-Villafranca, Lorente, Rivero, Iglesias, presentations and advice from: MSD, Schering-Plow, Ferring, Abbvie, Takeda, Herreros, Busquets, Riera, Martínez-Montiel, Roldón, Roncero, Hinojosa, Sierra, Janssen, Fresenius Kabi, Pfizer. IV has served as a speaker, or has received Barrio, De Francisco, Huguet, Merino, Carpio, Ginard, Muñoz, Piqueras, Almela, research or education funding from Abbvie, MSD, Pfizer, Takeda, Janssen, Tillotts Argüelles-Arias, Alcaín, Bujanda, Manceñido, Lucendo, Varela, Rodríguez-Lago, Pharma, Ferring and Shire Pharmaceuticals. MM has served as speaker or has Ramos, Sempere, Sesé, Barreiro-de Acosta, Domènech and Francés. This is an open- received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Takeda, access article distributed under the terms of the Creative Commons Attribution Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Biogen, License (CC BY). The use, distribution or reproduction in other forums is permitted, Tillotts Pharma, Chiesi and Adacyte. JPG has served as speaker, consultant, provided the original author(s) and the copyright owner(s) are credited and that the and advisory member for or has received research funding from MSD, Abbvie, original publication in this journal is cited, in accordance with accepted academic Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene, practice. No use, distribution or reproduction is permitted which does not comply Gilead/Galapagos, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, with these terms. Frontiers in Medicine | www.frontiersin.org 11 February 2022 | Volume 9 | Article 823900