Razonable realizar exámenes rutinarios para la EC en sujetos con SII
Un nuevo estudio realizado por investigadores de la Universidad Veracruzana, entre los que participa el doctor José María Remes Troche, llegó a la conclusión de que hasta el 5.2% de los pacientes con Síndorme de Intestino Irritable (SII), de acuerdo al criterio de Rome III, fueron positivos para por lo menos uno de los anticuerpos relacionados a la Enfermedad Celiaca (EC) y 2.5% tuvieron confirmación de la EC mediante una biopsia. Por lo tanto, indicaron los especialistas, aparenta ser una estrategia razonable realizar exámenes rutinarios para la EC en sujetos con SII, especialmente en el grupo SII-D, entre nuestra población.
En el estudio, publicado en la revista Neurogastroenterology & Motility en el pasado mes de marzo, participaron los doctores A. Sánchez Vargas, P. Thomas-Dupont, M. Torres-Aguilera, A. Azamar-Jácome, K. L. Ramírez Cervantes, M. R. Aedo-Garcés, A. Meixueiro-Daza, F. Roesch-Dietlen, P. Grube-Pagola, H. Vivanco-Cid y José Ma. Remes Troche, del Laboratorio de Motilidad Gastrointestinal y Psicología Digestiva; del Instituto Médico y de Investigaciones Biológicas de la Universidad Veracruzana, en el estado de Veracruz; del Doctorado en Ciencias Biomédicas en Jalapa, Veracruz y de la Facultad de Medicina Miguel Alemán Valdés, del Puerto de Veracruz.
Este nuevo protocolo del que ya hemos manejado algunos datos con anterioridad en Celiacos de México, destaca que:
- A pesar de que varios estudios proponen que análisis rutinarios de la enfermedad celiaca (EC) en individuos con síndrome del intestino irritable (SII)(específicamente SII-D y SII-M) está justificado, estudios recientes demuestran resultados controversiales en relación a este tema.
- En este gran estudio de caso y control (n=800) usando un control poblacional apareado por edad, sexo y una estrategia de anticuerpos múltiples (y sus combinaciones) con información histológica, encontramos que el OR para detectar la EC en individuos con SII fue 5.21.
- El subtipo SII_D tuvo la prevalencia más alta de positividad para h-tTG IgA y DGP II IgA, comparado con los otros subgrupos.
- De acuerdo con el análisis multivariante, ni el sexo y la edad ni tampoco el período de tiempo de progresión de los síntomas fue asociado con un mayor riesgo de la EC.
A continuación les presentamos un resumen de este protocolo que pueden leer completo en la parte baja de este artículo (en inglés)
Antecedentes: El costo-efectividad para análisis rutinarios de la enfermedad celiaca (EC) en pacientes con síndrome del intestino irritable (SII), específicamente en el subtipo diarrea (SII-D), es benéfico si la prevalencia es >1%. Sin embargo, estudios recientes han demostrado resultados controversiales. En este gran estudio de caso y control, nuestro objetivo era determinar la prevalencia de la EC y un panel de anticuerpos relacionados en pacientes diagnosticados con SII.
Materiales y métodos: Cuatrocientos pacientes con SII (Rome III) y 400 controles saludables y asintomáticos fueron prospectivamente evaluados usando anticuerpos antitransglutaminasa tisular (h-tTG IgA) y anticuerpos péptido desamidado de la gliadina (DGP II IgA y DGP II IgG). Se realizó una biopsia duodenal a los pacientes que fueron positivos a los anticuerpos h-tTG IgA y/o DGP II IgG.
Como resultados se obtuvo que:
La edad promedio de la población fue de entre 44.47 y 18.01 años; 335 (82%) de los individuos fueron mujeres. Veintiún pacientes y seis controles tuvieron por lo menos una prueba positiva para EC (5.25%). Dieciocho pacientes fueron positivos para h-tTG y/o DGP-II IgG.
La confirmación histológica de EC fue 2.5% en los pacientes de SII vs 0.5% en los controles (p = 0.04, OR 5.21). El subtipo SII-D tuvo la prevalencia más alta de positividad serológica (12.7%).
Por lo anterior, los investigadores llegaron a ls siguientes conclusiones:
Hasta el 5.2% de los pacientes con SII, de acuerdo al criterio de Rome III fueron positivos para por lo menos uno de los anticuerpos relacionados a la EC y 2.5% tuvieron confirmación de la EC mediante una biopsia. Por lo tanto, en nuestra población, el realizar exámenes rutinarios para la EC en sujetos con SII aparenta ser una estrategia razonable, especialmente en el grupo SII-D
Prevalence of celiac disease and related antibodies in patients diagnosed with irritable bowel syndrome according to the Rome III criteria. A case–control study
L. A. SANCHEZ-VARGAS ,*,† P. THOMAS-DUPONT,*,† M. TORRES-AGUILERA,* A. A. AZAMAR-JACOME,* K. L. RAMIREZCEERVANES,* M. R. AEDO-GARCES ,* A. MEIXUEIRO-DAZA,* F. ROESCH-DIETLEN,*,‡ P. GRUBE-PAGOLA,* H. VIVANCO-CID* & J. M. REMES-TROCHE*
‡ *Gastrointestinal Motility and Digestive Physiology Laboratory, Medical and Biological Research Institute of the Universidad Veracruzana, Veracruz, Veracruz, Mexico †Doctorate in Biomedical Sciences, Universidad Veracruzana, Xalapa, Veracruz, Mexico ‡Faculty of Medicine Miguel Aleman Valdes, Veracruz, Veracruz, Mexico
• Although several studies propose that routine screening for celiac disease (CD) in subjects with irritable bowel syndrome (IBS) (specifically IBS-D and IBS-M) is justified, recent studies have shown controversial results in relation to this theme.
• In this large case–control study (n = 800) using a control population paired by age and sex and a strategy of multiple antibodies (and their combinations) with histologic confirmation, we found that the OR for detecting CD in subjects with IBS was 5.21.
• The IBS-D subtype had the highest prevalence of positivity for h-tTG IgA and DGP II IgA, compared with the other subgroups.
• According to the multivariable analysis, neither sex, age nor the length of time of symptom progression was associated with an increased risk for CD
Background. The cost-effectiveness for screening for celiac disease (CD) in patients with irritable bowel syndrome (IBS), specifically in the diarrhea (IBS-D) subtype, is beneficial if the prevalence is >1%. However, recent studies have shown controversial results. In this large case–control study, our aim was to determine the prevalence of CD and a panel of related antibodies in patients diagnosed with IBS. Materials and methods Four hundred IBS patients (Rome III) and 400 asymptomatic healthy controls were prospectively evaluated using antihuman tissue transglutaminase (h-tTG IgA) and deamidated gliadin peptide antibodies (DGP II IgA and DGP II IgG). Duodenal biopsy was performed on the patients that were positive for the h-tTG IgA and/or DGP II IgG antibodies. Results The mean age of the population was 44.47 18.01 years and 335 (82%) of the subjects were women. Twenty-one patients and six controls had at least one positive test for CD (5.25% VS 1.5%, p = 0.003, OR 3.63 [95% CI 1.4–9.11]). Eighteen patients were positive for h-tTG and/or DGP-II IgG. Histologic confirmation of CD was 2.5% in the IBS patients vs 0.5% in the controls (p = 0.04, OR 5.21).
The IBS-D subtype had the highest prevalence for serological positivity (12.7%). Conclusions Up to 5.2% of the patients with IBS according to the Rome III criteria were positive for at least one of the CD-related antibodies and 2.5% had biopsy-confirmed CD. Therefore, in our population, screening for CD in subjects with IBS appears to be a reasonable strategy, especially in the IBS-D subgroup. Keywords celiac disease, diarrhea, gluten, irritable bowel syndrome, Mexico. INTRODUCTION Irritable bowel syndrome (IBS) is a very frequent functional gastrointestinal disorder and is estimated to affect between 9% and 18% of the general population.1 Numerous guidelines have proposed that additional diagnostic tests are not necessary in patients with typical symptoms and no alarm signs, because the probability of having an organic pathology is very low.1,2 However, celiac disease (CD), or gluten-sensitive enteropathy, is a clinical entity whose initial presentation can often manifest as symptoms similar to those of IBS, such as bloating and abdominal pain, and they are accompanied by alterations in stool frequency and/or consistency, predominantly in the form of diarrhea.3 A number of studies have suggested that carrying out CD screening tests in patients with symptoms suggestive of IBS could be a cost-effective and benefi- cial strategy, given that these reports have demonstrated that the prevalence of CD is higher in subjects diagnosed with IBS than in the general population.4–11 In a systematic review and a meta-analysis12 of 14 case–control studies in which 2278 individuals (58%) diagnosed with IBS were analyzed, it was determined that the prevalence of antibodies related to CD was four times higher than in a control population. The prevalence of IgA class antihuman tissue transglutaminase antibodies (h-tTG-IgA) and/or antiendomysial antibodies (anti-EMA) was 2.94% (95% CI 1.36–6.35), whereas the prevalence of histologically demonstrated CD was 4.1% (1.9–7.0). With such results, it is thought that close to 5% of the patients diagnosed with IBS could actually be subjects with CD.
Furthermore, two decision-analytic models have evaluated its cost-effectiveness and have concluded that this strategy is beneficial if the prevalence of the disease is >1%.13 Based on this evidence, the American College of Gastroenterology recommends routine screening for CD in subjects with IBS with diarrhea (IBS-D) and mixed IBS (IBS-M) (Grade 1B Recommendation).14 Nevertheless, recent studies have shown controversial results in relation to this theme. In a multicenter study (four centers) in the United States conducted on patients with non-constipated IBS, Cash et al.15 found that the prevalence of CD was similar to that of a control population (0.41% VS 0.44%, p = 0.99). In a recent study carried out on an open population, Choung et al.16 evaluated subjects with symptoms suggestive of functional gastrointestinal disorders and found that CD prevalence in that population was 1%. The aim of our study was to determine the prevalence of CD and the CD-related antibodies in a group of patients seen at a referral center that were diagnosed with IBS according to the Rome III criteria and to compare the results with a control group that was paired by age and sex.
Consecutive patients that sought medical attention for gastrointestinal symptoms suggestive of IBS (abdominal pain and/or bloating) at the Medical and Biological Research Institute of the Universidad Veracruzana (a tertiary care center) within the time frame of 1 December 2010 and 30 June 2012 were prospectively evaluated. Subjects were included that met the Rome III Criteria for IBS (validated Spanish version) and in whom alarm signs (anemia, weight loss, fever, etc.) were ruled out in the clinical evaluation.17 Clinical evaluation included background, a symptom questionnaire administered at the clinic, physical examination, and baseline investigations (complete blood count, erythrocyte sedimentation rate, thyroid function, C-reactive protein and glucose). Patients with previous diagnoses of cancer, thyroid diseases, diabetes mellitus, inflammatory bowel disease, CD, or a history of major abdominal surgery (with the exception of cholecystectomy or appendectomy) were excluded. The control group was made up of asymptomatic healthy controls (in accordance with physical examination and clinical evaluation) and they were paired by age and sex. These subjects were recruited from an open population (same geographical region) and their samples had been previously collected for population studies in the Veracruz-Boca del Rıo region at a center that performed routine medical check-ups and premarital evaluations. All the control subjects answered the Rome III questionnaire to confirm the absence of IBS symptoms.
Protocol After giving their informed consent, the subjects were sent to the Department of Digestive Physiology of the Medical and Biological Research Institute of the Universidad Veracruzana to undergo the diagnostic tests. A total of 5 mL of blood was drawn from all the subjects. The serum was separated to perform the h-tTG IgA and deamidated gliadin peptide (DGP II IgA and DGP II IgG) tests through the ELISA technique (INOVA QUANTA h-tTG IgA, INOVA QUANTA Lite TM DGP II IgA and INOVA QUANTA Lite TM DGP II IgG [Inova Diagnostics, San Diego, CA, USA]). Titers under 20 IU were considered negative, 20–30 weakly positive, and >30 IU frankly positive. Patients with h-tTG IgA and/or DGP II IgG levels above the reference range were considered positive and they were offered an esophagogastroduodenoscopy so that at least four biopsy samples could be taken from the duodenum (two from the bulb and two from the distal duodenum) in order to evaluate the presence of histologic findings consistent with CD. The combination of the h-tTG IgA and DGP II IgG antibodies had a positive predictive value of 100% and a negative predictive value of 98.8%.18,19,20 The biopsy samples were fixed in formalin at 19%, stained with H&E, and then evaluated by an expert pathologist (PG). The Marsh-Oberhuber classification was € used and CD diagnosis was made when the classification was above stage I.21
Statistical analysis Considering that the prevalence of CD in our population was 0.59%22 and its prevalence in patients with IBS was 4.1% in the meta-analysis conducted by Ford,12 it was established that the sample would need to be made up of at least 385 patients and 385 controls. Type I error probability associated with the test of this null hypothesis was 0.05. Descriptive statistics were carried out and CD prevalence and positivity for the antibodies described above were calculated in patients with IBS and in healthy controls. Prevalence was compared through the chi-squared test or the Fisher’s exact test, as appropriate. The odds ratios (OR) and 95% confidence intervals (95% CI) were estimated. Differences between IBS subtypes were calculated using the one-way ANOVA with the Bonferroni correction. Kendall’s tau coefficient was calculated to correlate the number of positive tests for CD (1 positive = either h-tTG IgA or DGP II IgA, 2 positive = any combination of h-tTG IgA, DGP II IgA, and/or DGP II IgG, 3 positive = all tests positive) and the Marsh-Oberhuber histologic € classification among the subjects that agreed to undergo endoscopic biopsies. The demographic characteristics were then compared between the patients with IBS and histologically confirmed CD and the patients with IBS and no CD. Finally, the results were adjusted according to sex, age, and IBS subtype through logistic regression. The analysis was done with SPSS version 14 (Chicago, IL, USA) software. This project was approved by the research and ethics committee of the Medical and Biological Research Institute of the Universidad Veracruzana.
RESULTS A total of 400 subjects with IBS and 400 healthy controls were evaluated. Table 1 shows the demographic characteristics of the evaluated subjects. It should be mentioned that our entire population was classified as Hispanic (Mexican Mestizos) and did not include any other race. The mean length of time the patients had symptoms associated with IBS was 76.4 33 months. A total of 220 patients had IBS-M (55%), 124 irritable bowel syndrome-constipation predominant (IBS-C; 31%), and 56 IBS-D (14%). Table 2 shows the demographic characteristics according to the IBS subtypes.
CD-related antibody detection
Twenty-one patients and six controls had at least one positive test for CD (5.25% vs 1.5%, p = 0.003, OR 3.63 [95% CI 1.4–9.11]). The prevalence of positive antibodies in the patients and controls is shown in Table 3. Fourteen patients with IBS (3.5%, 95% CI 1.62.6–6.9) and three controls (0.75%, 95% CI 0.2–2.1; OR 4.79 (1.3–16.4) p = 0.014) were positive for h-tTG antibodies. The IBS patients had a significantly higher prevalence of positivity for DGP II IgA, compared with the controls (3% vs 0.75%, OR 4.09 [95% CI 1.14–14.6], p = 0.018). There was no difference in relation to the DGP II IgG antibodies between the two groups. The prevalence of low IgA levels was 1.0% (n = 4) in the patients with IBS and 0.3% (n = 1) in the control group (p = 0.17). Table 4 shows the different combinations of CD-positive antibodies found in the IBS patients. The patients with the IBS-D subtype had the highest prevalence of positivity for h-tTG IgA (12.7%) and DGP II IgA (12.7%), compared with the other subgroups (p < 0.02, see Table 3). The multinomial logistic regression analysis that included sex, age, length of time of symptom progression, and subtypes, revealed a statistically significant difference only for the IBS-D subtype (Wald 7.92, Exp [B] 0.153, significance 0.005). Eighteen patients were positive for h-tTG and/or DGP II IgG. Thirteen patients and three controls with positive for h-tTG IgA and/or DGP II IgG and they agreed to undergo duodenal biopsy. Of the patients with IBS and biopsy-confirmed CD, eight had IBS-D (62%), three had IBS-M (23%), and two had IBS-C (15%). Histology suggested CD in 3.25% of the patients (n = 13) and in 0.75% (n = 3) of the controls (p = 0.02, OR 4.44, 95% CI 1.29–16.14). However, 10 patients and two controls had a Marsh-Oberhuber € classification higher than I (2.5% VS 0.5%, p = 0.041, OR 5.21, 95% CI 1.13–2.93). The presence of a Marsh-Oberhuber grade III or higher histologic damage was € found only in the IBS patients (1.25% vs 0%, p = 0.07). Distribution of the Marsh-Oberhuber classification € among groups is shown in Table 5. A significant positive correlation (r = 0.597, p = 0.011) between the Marsh-Oberhuber classification and the number of € positive tests for CD was found.
According to our results, the prevalence of CD in our cohort of IBS patients was 2.5–3.25% (determined through histology or serology), confirming the observations made in previous meta-analyses and studies. Our findings were similar to those reported in the United Kingdom,4,8 Sweden,7 Germany,23 Italy,24 Iran,6 Latvia,25 and Turkey.10 Therefore, looking for CD in patients that have refractory IBS symptoms, especially those that present with the diarrhea subtype, also appears to be justified in a Hispanic population such as ours. Although the most recent studies in the United States call into question the justification of searching for CD15,16 in patients with IBS (especially with IBS-D), the data obtained in our study are the result of a methodology that included: an appropriate sample size, a control population paired by age and sex, the selection of patients seen at a referral center, the use of the Rome III criteria, an analysis by subtype, the use of multiple antibodies (and their combinations) for diagnosing CD, and histologic confirmation in an important number of subjects. The control population in CD studies is an ongoing problem due to the risk for bias. In the largest multicenter study on this theme conducted in the United States, Cash et al. 15 found that CD prevalence was similar in patients with non-constipated IBS and a control population, but the characteristics of the controls were one of the main limitations of their study. Their control population was made up of older subjects (a mean of 54 years) undergoing screening studies for colon cancer and there was a predominance of men (59%). In our study we decided to use a control population that was paired by age and sex, so that our sample would represent the ‘typical’ profile of the patients that suffer from IBS, in other words, patients that are predominantly women (85%) in the fifth decade of life (mean age 44 years). As in other studies,20,26,27 we decided to use subjects that were being seen for general health check-ups or that were undergoing a premarital physical evaluation. On the other hand, in a study on an open population with gastrointestinal symptoms evaluated through the BDQ questionnaire in Olmstead County, Choung et al. 16 demonstrated that CD screening was not an appropriate strategy, due to the low prevalence found (1%). In effect, we agree that this strategy is not appropriate in the general population. It is our opinion (the same as that expressed in other studies) that CD should be looked for in IBS patients that present with symptoms that are difficult-to-control or refractory (especially in those patients with the IBS-D subtype). This is the type of patient that is typically seen in referral centers such as ours, and therefore we consider that this population should be susceptible to CD screening in the context of IBS. For example, in the meta-analysis by Ford,12 the OR for detecting CD in patients with IBS through EMA or tTG testing was 1.97 (95% CI 0.60–6.43) at the primary care level, but it was almost double at 3.99 (1.04–15) when studies conducted at referral centers (secondary care level) were taken into account. It is important to mention that once the guidelines for primary care IBS management begin to recommend serologic screening for CD in patients meeting the criteria for IBS, if primary care practitioners adhere to such recommendations, the yield of testing in secondary and tertiary care centers may start to decline. The majority of the previous studies have included patients that were diagnosed with IBS based on either clinical criteria or the Rome II criteria.12,15,16 Some studies have even failed to evaluate patients according to IBS subtypes. As we showed in our analysis, this is of the utmost importance, given that the probability of having CD, rather than IBS, is significantly higher in those patients presenting with diarrhea-predominant IBS. The prevalence of CD found in our study in subjects with IBS according to the Rome III criteria was similar to that reported in more recent studies using the same criteria, such as the study by Patel et al.28 in Canada that reported a prevalence of 2.9%, or the Iranian study by Bakhshipour A, in which prevalence was 5.5%.29 One of the limitations of our study was not having employed a sequential strategy for the serologic diagnosis of CD, that is to say, not having later carried out the anti-EMA test on the patients that were positive for h-tTG IgA. That strategy has shown adequate sensitivity and specificity and has been used in the studies by Choung and Cash.15,16 EMA determination in our population is not widely available because of its high cost, and so the strategy for establishing probable CD diagnosis in our patients with IBS was based on their being positive for h-tTG IgA only, or a combination of that antibody and DGP II IgG positivity. In accordance with different guidelines, the initial test of choice for looking for CD should be the h-tTG IgA test,14,30 whereas the DGP II IgG test is highly recommended when IgA deficiency is suspected.14,30,31 In addition, the combination of h-tTG IgA + DGP II IgG has been shown to have a sensitivity and specificity for CD diagnosis of 90–96% and 96–100%, respectively,20 whereas the ‘sequential testing paradigm’ has a 97% sensitivity and a 100% specificity.32 In contrast to other studies, we had the opportunity to take duodenal biopsies in an important percentage (72%) of our cases (13 of 18 subjects with positive htTG and/or DGP II IgG antibodies), thus CD was histologically confirmed. In our study, the histologic diagnosis of CD was very similar to that reported previously by Ford et al.12 Compared with the studies by Sanders et al.7 and Cash et al., 11 we used a more precise histologic definition for CD. We considered that a patient had biopsy-confirmed CD if he or she had a Marsh-Oberhuber classification higher than I, thus € excluding patients with other causes of intraepithelial lymphocytosis (such as Helicobacter pylori infection, bacterial overgrowth, nonsteroidal anti-inflammatory drug damage, tropical sprue, and chronic inflammatory bowel disease). It is important to mention that 38% of our biopsied cases (n = 5) had a histologically advanced lesion (villous atrophy), without having apparent alarm signs, such as weight loss or anemia. None of the biopsied controls had a Marsh-Oberhuber classification € higher than III. Therefore, according to our results, between 2.5% (Marsh-Oberhuber € >I) and 1.25% (Marsh-Oberhuber € ≥III) of IBS patients had biopsyconfirmed CD. Our study also had the limitation of not having evaluated the prevalence of other disorders related to gluten ingestion, such as non-celiac gluten sensitivity (NCGS).33 Even though this was not the primary aim of our study, it would have been interesting to determine the prevalence of this recently described entity. NCGS is characterized by a heterogeneous clinical picture, with intestinal and extraintestinal symptoms arising after gluten ingestion and rapidly improving when it is withdrawn from the diet.33,34 There is some overlap between IBS and NCGS. In fact, in patients meeting the Rome III criteria for IBS, mainly in those with diarrhea in both the predominant and mixed forms, NCGS has been diagnosed in a high percentage of cases and they have been subgrouped as having glutensensitive IBS.35,36 Nevertheless, the true prevalence of NCGS in patients with IBS and its clinical implications are still subjects of debate. Another limitation was not having determined the DQ2/DQ8 haplotypes of the major histocompatibility complex.14 However, human leukocyte antigen DQ2/ DQ8 testing should not be used routinely in the initial diagnosis of CD, but rather to effectively rule out the disease in selected clinical situations such as: when there are equivocal small bowel histologic findings (Marsh I–II) in seronegative patients, in the evaluation of patients on a gluten-free diet that were not tested for CD before the diet, and in patients with discrepant celiac-specific serology and histology.14 Finally, we did not assess other risk factors associated with an increased/decreased risk for CD, such as a family history of CD, or concomitant conditions, such as thyroid conditions (these patients were excluded), hypertension, and hypercholesterolemia.26 In conclusion, based on our results, up to 5.25% of the patients with IBS according to the Rome III criteria were positive for either h-tTG IgA or DGP II IgA antibodies, or both. Specifically, 3.5% were positive for h-tTG IgA antibodies and 2.5% had biopsy-confirmed CD. Therefore, we believe that screening for CD in subjects with IBS appears to be a reasonable strategy in our population, especially in the IBS-D subgroup.
The authors thank Gusti Gould for her editorial work and translation of this document, Virgilio Gonzalez-Velazquez from IL Diagnostics, SA de CV for his support in the acquisition of the serologic tests, and Kaz Nakanishi and Dr Gary Norman from INOVA Dx for their support in choosing the best serologic strategy for establishing celiac disease.
This work was supported by the Fondo Sectorial en Investigacion Basica SEP-CONACyT Project ID 134884. Sanchez-Vargas LA and Thomas-Dupont P were recipients of PhD scholarships from the CONACyT, Mexico, No. 279133 and 279061, respectively.
LAS-V, HV-C, and JMR-T contributed to the outlining of the study, generation, collection, assembly, analysis, and/or interpretation of data; PT-D and LAS-V performed the research and analyzed the blood samples; MT-A, AAA-J, MRA, AM-D, R-C, and FR-D contributed to the generation, collection and analysis of clinical data and assembly of data; PG-P performed the histologic analysis; JMR-T reviewed and wrote the paper. All authors approved the final version of the manuscript.
Jose Marıa Remes-Troche is a member of the Advisory Board for Takeda Pharmaceuticals, Alfa-Wassermann, Almirall, and Janssen. He is also a Speaker for Nycomed-Takeda, Advance Medical, Endomedica, Astra-Zeneca, and Bristol-Myers-Squibb. The other authors do not have conflicts of interest.
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