Editorial: Personalizing Treatment in IBD: Hype or Reality in 2020?

[No abstract available

Thiopurines in inflammatory bowel disease. How to optimize thiopurines in the biologic era?

Thiopurines have been a cornerstone in the treatment of inflammatory bowel disease (IBD). Although they have been used for more than 50 years, there are still some unsolved issues about their efficacy and, also, some safety concerns, mainly the risk of myelosuppression and life-threatening lymphoproliferative disorders. Furthermore, the development of biological therapy raises the question whether there is still a role for thiopurines in the IBD treatment algorithm. On the other hand, limited cost and wide availability make thiopurines a reasonable option in settings of limited resources and increasing prevalence of IBD. In fact, there is a growing interest in optimizing thiopurine therapy, since pharmacogenomic findings suggest that a personalized approach based on the genotyping of some molecules involved in its metabolism could be useful to prevent side effects. Polymorphisms of thiopurine methyltransferase enzyme (TPMT) that result in low enzymatic activity have been associated with an increased risk of myelotoxicity, especially in Caucasians; however, in Asians it is assumed that the variants of nudix hydrolase 15 (NUDT15) are more relevant in the development of toxicity. Age is also important, since in elderly patients the risk of complications seems to be increased. Moreover, the primo-infection of Epstein Barr virus and cytomegalovirus under thiopurine treatment has been associated with severe lymphoproliferative disorders. In addition to assessing individual characteristics that may influence thiopurines treatment outcomes, this review also discusses other strategies to optimize the therapy. Low-dose thiopurines combined with allopurinol can be used in hypermethylators and in thiopurine-related hepatotoxicity. The measurement of metabolites could be useful to assess compliance, identify patients at risk of adverse events and also facilitating the management of refractory patients. Thioguanine is also a rescue therapy in patients with toxicity related to conventional thiopurine therapy. Finally, the current indications for thiopurines in monotherapy or in combination with biologics, as well as the optimal duration of treatment, are also reviewed. © Copyright © 2021 Gargallo-Puyuelo, Laredo and Gomollón

Bioequivalence studies with anti-TNF biosimilars

Introduction: Biosimilars, as defined by the European Medicines Agency, have been used in Europe since 2006. The landscape was considerably expanded when the first biosimilar of a monoclonal was approved and introduced in the European market. CT-P13 was developed by Celltrion as an infliximab biosimilar in 2013, not without controversy. As these complex molecules cannot be completely identical, some experts, clinicians, and even patients were skeptical regarding the real bioequivalence of the drugs. Currently, several new infliximab and adalimumab biosimilars are available or will reach the market in a few months. Areas covered: Our goal is to review, mainly from a clinical perspective, the available evidence for bioequivalence of anti-TNF biosimilars. We aim to take into account not only preclinical studies, mostly done for regulatory issues, but also data from clinical studies. Expert opinion: We can conclude that bioequivalence with originator is well demonstrated in those drugs which have followed European Medicines Agency regulatory pathways. Switching from originator to biosimilar appears safe for all indications. However, there are few data available for switching from one biosimilar to another, or for complete interchangeability. Prospective studies and strict pharmacovigilance are recommended

El papel de los biosimilares en la enfermedad inflamatoria intestinal: Una realidad en nuestro país

La Enfermedad Inflamatoria Intestinal (EEI) es un término con el que se conocen varias entidades, las dos más importantes: la Colitis Ulcerativa Idiopática (CUI) y la Enfermedad de Crohn (EC), cuyo origen es multifactorial y se caracterizan por un fenómeno inflamatorio, crónico, recurrente con diferentes grados de severidad del tubo digestivo; pero además con afectación potencial de otros órganos. En la última década ha habido un renovado interés en dichas entidades, debido a una incidencia creciente de estas pero también debido al desarrollo de medicamentos que por primera vez están cambiando la historia natural de estas enfermedades; son los medicamentos llamados biológicos, que son aquellos producidos o derivados de organismos vivos y representan el sector de mayor crecimiento en la industria farmacéutica mundial. Debido al interés comercial se han desarrollado y sometido a las autoridades reguladoras productos no originadores, similares pero no idénticos a los productos de referencia. La Agencia Europea Reguladora de Medicamentos aprobó el primer biosimilar del infliximab, para todas las indicaciones en las cuales este estaba aprobado; incluidas: Colitis Ulcerativa (CU) moderada a severa en todas las edades, Enfermedad de Crohn (EC) moderada a severa en todas las edades, al igual que EC fistulizante, Artritis Psoríasica (AP), Psoriasis (P), Espondilitis Anquilosante (EA), y en Artritis Reumatoide (AR) (6). En esta revisión nos proponemos definir lo que son estos productos al igual de unos conceptos acuñados al uso de estos (extrapolación, sustitución e intercambiabilidad), además hacer una revisión histórica de su desarrollo, sus indicaciones actuales las posiciones de las diferentes asociaciones científicas con respecto a estos y lo más importante brindar datos de la vida real en cuanto a su efectividad, seguridad y costos en los diferentes países en donde se han estado usando. The term Inflammatory Bowel Disease (IBD) is used to identify several entities, the two most important of which are Idiopathic Ulcerative Colitis (IUC) and Crohn’s Disease (EC). Both are multifactorial in origin, are chronic and recurrent, are characterized by inflammation, have varying degrees of severity, and potentially involve other organs. In the last decade there has been renewed interest in these entities due to growing incidence and to the development of drugs called biologicals. For the first time, these drugs have changed the natural history of these diseases. They are produced or derived from living organisms and represent the fastest growing sector in the global pharmaceutical industry. Due to commercial interest, products similar but not identical to the original products have been developed and submitted to regulatory authorities. The European Medicines Agency has approved the first biosimilar for infliximab for all indications for which it has been approved. These include moderate to severe ulcerative colitis (UC) at all ages, moderate to severe Crohn’s disease (CD) at all ages, fistulizing Crohn’s disease, Psoriasic arthritis, Psoriasis, Ankylosing Spondylitis, and Rheumatoid Arthritis. In this review, we define what these products are, as well as some concepts coined for their usage including extrapolation, substitution and interchangeability. We also make a historical review of their development, current indications, the positions of various scientific associations with respect to them, and - most importantly - provide real-life data regarding their effectiveness, safety and costs in countries where they have been used

Small and large intestine (II): Inflammatory bowel disease, short bowel syndrome, and malignant tumors of the digestive tract

The small intestine is key in the digestion and absorption of macro and micronutrients. The large intestine is essential for the absorption of water, to allow adequate defecation, and to har-bor intestinal microbiota, for which their nutritional role is as important as it is unknown. This article will describe the causes and consequences of malnutrition in patients with inflammatory bowel diseases, the importance of screening and replacement of micronutrient deficits, and the main indi-cations for enteral and parenteral nutrition in these patients. We will also discuss the causes of short bowel syndrome, a complex entity due to anatomical or functional loss of part of the small bowel, which can cause insufficient absorption of liquid, electrolytes, and nutrients and lead to complex management. Finally, we will review the causes, consequences, and management of malnutrition in patients with malignant and benign digestive tumors, including neuroendocrine tumors (present not only in the intestine but also in the pancreas). © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Are Steroids Still Useful in Immunosuppressed Patients With Inflammatory Bowel Disease? A Retrospective, Population-Based Study

Background: Effectiveness of corticosteroids in immunosuppressed patients with inflammatory bowel disease (IBD) has not been completely elucidated. Aims: To assess the effectiveness and examine the long-term follow-up of systemic or low-bioavailability oral steroid treatment for moderate flare-ups in patients treated with immunosuppressive drugs. Methods: Immunosuppressed patients with inflammatory bowel disease (IBD) from our population-data registry were analyzed. For statistical analysis, the chi-square test, Mann-Whitney U test, and Kaplan-Meier survival analysis were used as appropriate. Results: A total of 392 patients with IBD and a median of 82 (range, 6–271) months of immunosuppressive (IMM) treatment were identified. The mean follow-up was 87 months (range, 6–239 months). A total of 89 patients (23%) needed at least one steroid course during their follow-up. Average time from IMM to steroid treatment was 26 (range, 6–207) months. In patients with CD, fibrostenotic (B2) and fistulizing (B3) behaviors [p = 0.005; odds ratio (OR): 2.284] were risk factors for using steroids after IMM treatment. In patients with UC, no statistically significant variables were identified. Of the 89 patients who received one first steroid course, 49 (55%) stepped up to biological treatment or surgery after a median of 13 months (range, 0–178), 19 (21%) were treated with repeated steroid courses, and 31 (35%) required no further treatment. Patients with CD had a higher risk (p = 0.007; OR: 3.529) of receiving biological treatment or surgery than patients with UC. The longer the patients with UC (more months) spent using steroids, the greater the risk of requiring treatment with biological drugs or surgery (p = 0.009). Conclusion: A total of 23% of the immunosuppressed patients with IBD received at least one course of steroid treatment. In patients under immunosuppression treated with at least a course of steroids, CD patients were more likely stepped up to biologics and/or surgery than UC patients. In patients with CD, B2/B3 behavior pattern were significant risk factors. After one course of steroids only 35% of immunosuppressed IBD patients remained in remission without needing treatment scalation. © Copyright © 2021 Sicilia, Arias, Hontoria, García, Badia and Gomollón

Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation

This is the final version of the article. Available from Public Library of Science via the DOI in this record.TLR2 is a microbiota recognition receptor that has been described to contribute to intestinal homeostasis and to ameliorate inflammatory intestinal injury. In this context, serotonin (5-HT) has shown to be an essential intestinal physiological neuromodulator that is also involved in intestinal inflammatory diseases. Since the interaction between TLR2 activation and the intestinal serotoninergic system remains non-investigated, our main aim was to analyze the effect of TLR2 on intestinal serotonin transporter (SERT) activity and expression and the intracellular pathways involved. Caco-2/TC7 cells were used to analyze SERT and TLR2 molecular expression and SERT activity by measuring 5-HT uptake. The results showed that apical TLR2 activation inhibits SERT activity in Caco-2/TC7 cells mainly by reducing SERT protein level either in the plasma membrane, after short-term TLR2 activation or in both the plasma membrane and cell lysate, after long-term activation. cAMP/PKA pathway appears to mediate short-term inhibitory effect of TLR2 on SERT; however, p38 MAPK pathway has been shown to be involved in both short- and long-term TLR2 effect. Reciprocally, 5-HT long-term treatment yielded TLR2 down regulation in Caco-2/TC7 cells. Finally, results from in vivo showed an augmented intestinal SERT expression in mice Tlr2-/-, thus confirming our inhibitory effect of TLR2 on intestinal SERT in vitro. The present work infers that TLR2 may act in intestinal pathophysiology, not only by its inherent innate immune role, but also by regulating the intestinal serotoninergic system.This work was funded by grants from the Spanish Ministry of Science and Innovation and the European Regional Development Fund (ERDF/FEDER) (BFU2010-18971), Zaragoza University (UZ2014-BIO-03), European Social Found (ESF) and the Aragon Regional Government (B61) and the Foundation for the Study of Inflammatory Bowel Diseases in Aragón (ARAINF 012/2008). ARAID Foundation supported J.P. (SAF2014-54763-C2-1-R) and E. Layunta is a PhD student fellow from Aragon Regional Government (B022/13). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

La enfermedad inflamatoria intestinal y los riesgos de enfermedad cardiovascular

La enfermedad inflamatoria intestinal (EII), comprende tanto a la colitis ulcerosa como a la enfermedad de Crohn, entidades consideradas enfermedades inmunomediadas, sistémicas y de curso crónico que conllevan a menudo el desarrollo de manifestaciones extraintestinales. A pesar de que el estudio de las comorbilidades haya sido desarrollado tradicionalmente en contexto de otras enfermedades inflamatorias sistémicas, este concepto está emergiendo también en la EII. Multitud de patologías han sido vinculadas a la EII, entre las que destaca la enfermedad cardiovascular, la primera causa de muerte en los países desarrollados. Los pacientes con EII están expuestos a un mayor riesgo de entidades tales como arterosclerosis precoz e infarto de miocardio, o trombosis venosas y tromboembolismo pulmonar. El objetivo de esta revisión es hacer una aproximación a la fisiopatología de las diferentes manifestaciones de la enfermedad cardiovascular en los pacientes con EII y de cómo prevenirlas. Inflammatory bowel disease (IBD) includes both ulcerative colitis and Crohn's disease, which are well recognised as chronic systemic and immune-mediated conditions that frequently involve extraintestinal manifestations. Although comorbidities have long been the subject of research in other chronic inflammatory diseases, this concept is also emerging in IBD. Many pathologies have been linked to IBD, including cardiovascular disease, which is the main cause of death in developed countries. IBD patients are at increased risk of conditions such as early atherosclerosis and myocardial infarction or venous thrombosis and pulmonary thromboembolism. The aim of this review is to make an approximation of the physiopathology of the different manifestations of cardiovascular disease in patients with IBD and how to prevent them

A patient self-made point-of-care fecal test improves diagnostic accuracy compared with fecal calprotectin alone in inflammatory bowel disease patients

Background: Monitoring inflammatory bowel disease patients may be challenging. Fecal calprotectin is one of the most performed tests. Other fecal biomarkers are less used in clinical practice. Rapid fecal tests that could be performed by patients may be a useful strategy to closely monitor disease activity. Methods: We performed a prospective observational study including consecutive inflammatory bowel disease patients referred for colonoscopy in a single center. Certest FOB + Transferrin + Calprotectin + Lactoferrin® (Certest Biotec S.L, Zaragoza, Spain), a one-step point-of-care test which simultaneously detects these four biomarkers was performed. Endoscopic inflammatory activity was defined using the Mayo score (=1) in ulcerative colitis, SES-CD (>3) and Rutgeerts scores (=1) for Crohn’s disease. Results: Out of a total of 106 patients (56.5% female, mean age 51 years), 54 (50.9%) were diagnosed with ulcerative colitis and 52 (49.1%) with Crohn’s disease. Endoscopic activity was detected in 42 patients (39.0%). Fecal calprotectin provided the best sensitivity (97.6%), with limited specificity (34.4%). Compared to calprotectin, the other 3 fecal biomarkers showed better specificity (87.5–92.1%) and lower sensitivity (45.2–59.5%). Patients with a negative result in all biomarkers (19/106—17.9%) had 100% (CI 95% 97.4–100) negative predictive value, while patients with the 4 biomarkers positive (13/106—12.3%) had 100% (CI 95% 96.1–100) positive predictive value of endoscopic inflammatory activity. AUROC of this 4 biomarker point-of-care test was 0.845 (95% CI 0.771–0.920), significantly higher than the AUROCs of any of the 4 biomarkers. Conclusions: This test may be a useful strategy to monitor inflammatory activity in clinical practice by excluding or prioritizing patients in need of a colonoscopy. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Oral cyanocobalamin is effective in the treatment of vitamin B12 deficiency in crohn’s disease

Cobalamin deficiency is common in patients with Crohn’s disease (CD). Intramuscular cobalamin continues to be the standard therapy for the deficiency and maintenance treatment in these patients, although oral route has been demonstrated to be effective in other pathologies with impaired absorption. Our aims were to evaluate the efficacy of oral therapy in the treatment of cobalamin deficiency and in long-term maintenance in patients with Crohn’s disease. We performed a multicenter retrospective cohort study that included 94 patients with Crohn’s disease and cobalamin deficiency. Seventy-six patients had B12 deficiency and 94.7% of them normalized their cobalamin levels with oral treatment. The most used dose was 1 mg/day, but there were no significant differences in treatment effectiveness depending on the dose used (=1 mg/24 h vs. <1 mg/24 h). Eighty-two patients had previous documented B12 deficiency and were treated with oral B12 to maintain their correct cobalamin levels. After a mean follow-up of 3 years, the oral route was effective as maintenance treatment in 81.7% of patients. A lack of treatment adherence was admitted by 46.6% of patients in who the oral route failed. In conclusion, our study shows that oral cyanocobalamin provides effective acute and maintenance treatment for vitamin B12 deficiency caused by CD with or without ileum resection