Evolution After Anti-TNF Discontinuation in Patients With Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study.

OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed. METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included. RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07-3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe. CONCLUSIONS: The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe.

Safety of thiopurines and anti-TNF-α drugs during pregnancy in patients with inflammatory bowel disease.

OBJECTIVES: The safety of thiopurines and anti-tumor necrosis factor-α (TNF-α) drugs during pregnancy remains controversial, as the experience with these drugs in this situation is limited. Our aim is to assess the safety of thiopurines and anti-TNF-α drugs for the treatment of inflammatory bowel disease (IBD) during pregnancy. METHODS: Retrospective, multicenter study in IBD patients. Pregnancies were classified according to the therapeutic regimens during pregnancy or during the 3 months before the conception: non-exposed group, pregnancies exposed to thiopurines alone (group A), and pregnancies exposed to anti-TNF-α drugs (group B). An unfavorable Global Pregnancy Outcome (GPO) was considered if pregnancy developed with obstetric complications in the mother and in the newborn. RESULTS: A total of 187 pregnancies in the group A, 66 pregnancies in the group B, and 318 pregnancies in the non-exposed group were included. The rate of unfavorable GPO was different among the three groups (31.8% in non-exposed group, 21.9% in group A, and 34.8% in group B), being lower in pregnancies under thiopurines than among non-exposed (P = 0.01). The rate of pregnancy complications was similar among the three groups (27.7% in non-exposed, 20.9% in group A, and 30.3% in group B). The rate of neonatal complications was different among the three groups (23.3% in non-exposed group, 13.9% in group A, and 21.2% in group B), being lower in pregnancies under thiopurines than among non-exposed (P = 0.01). In the multivariate analysis, the treatment with thiopurines (odds ratio = 0.6; 95% confidence interval = 0.4-0.9, P = 0.02) was the only predictor of favorable GPO, whereas maternal age >35 years at conception was the only predictor of unfavorable GPO. The treatment with anti-TNF-α drugs was not associated with an unfavorable GPO. CONCLUSION: The treatment with thiopurines and anti-TNF-α drugs does not seem to increase the risk of complications during pregnancy and does seem to be safe for the newborn.

UAV-borne LiDAR revolutionizing groundwater level mapping.

In hydrogeological research, the systematic and periodic measurement of the piezometric level is fundamental to assess aquifer storage, identify recharge and discharge areas, define flow directions and to infer the balance between inputs and withdrawals. Furthermore, knowledge of this variable and its fluctuations is essential for the efficient management and protection of groundwater resources. In this work, a novel methodology is proposed for the remote acquisition of piezometric information from traditional large-diameter wells, using drone-borne LiDAR observations. The workflow developed consists of different stages, from flight planning and parameter setting, to point cloud generation, data processing and validation and its statistical treatment to extract piezometric information. This methodology has been applied in a small coastal aquifer with numerous wells that have served as monitoring points. The UAV-LiDAR has enabled the straightforward obtention of measurements of the piezometric level with very high vertical accuracies (RMSE of 5 cm) with minimum and maximum residuals of -8.7 and 7.9 cm respectively. Likewise, the method has shown vertical accuracies 3 times better than those inferred from the official DTM of best resolution available in Spain, which is usually used in hydrogeological works. Since the technique provides absolute values of the piezometric level, it eliminates the need for laborious levelling work prior to hydrogeological campaigns. This method has proved to be an effective alternative/complementary technique to traditional measurements of the piezometric level, allowing to monitor extensive or inaccessible areas over short periods of time and to potentially reduce gaps in hydrogeological databases.

Real-world short-term effectiveness of ustekinumab in 305 patients with Crohn's disease: results from the ENEIDA registry.

BACKGROUND: There are limited data of ustekinumab administered according to the doses recommended in the UNITI studies. AIM: To assess the real-world, short-term effectiveness of ustekinumab in refractory Crohn's disease (CD) METHODS: Multicentre study of CD patients starting ustekinumab after June 2017 at the recommend dose (260, 390 or 520 mg based on weight ~6 mg/kg IV week 0 and 90 mg subcutaneously week 8). Values for Harvey-Bradshaw Index (HBI), C-reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 8 and 14. Demographic and clinical data, previous treatments, AEs and hospitalisations were documented. Possible predictors of clinical remission were examined. RESULTS: Three hundred and five patients were analysed (≥2 previous anti-TNFα therapies 64% and vedolizumab 29%). At baseline, 217 (72%) had an HBI >4 points. Of these, 101 (47%) and 126 (58%) achieved clinical remission at weeks 8 and 14, respectively. FC levels returned to normal (<250 µg/g) in 46% and 54% of the patients at weeks 8 and 14 respectively. CRP returned to normal (<3 mg/L) in the 35% and 41% of the patients at week 8 and 14 respectively. AEs were recorded in 38, and 40 patients were hospitalised. Intolerance to the most recent anti-TNF agent and fewer previous anti-TNF agents were associated with clinical remission at week 14. Endoscopic severity was associated with poor response. CONCLUSION: This is the first study to show the real-world effectiveness and safety of ustekinumab administered according to the recommended induction regimen in a cohort of highly refractory CD patients.

Prevalence and Factors Associated With Fatigue in Patients With Inflammatory Bowel Disease: A Multicentre Study.

BACKGROUND AND AIMS: The aims of this study were to determine the prevalence of fatigue in patients with inflammatory bowel disease [IBD], to identify the factors associated with fatigue and its severity, to assess the impact of fatigue on quality of life [QoL], and to evaluate the relationship between fatigue and sleep disorders. METHODS: This was a prospective multicentre study conducted at 22 Spanish centres. Consecutive patients followed at IBD Units were included. Fatigue was evaluated with the Fatigue Severity Scale [FSS] and the Fatigue Impact Scale [FIS]. Quality of life and sleep quality were assessed using the IBD Questionnaire-Short Form [IBDQ-9] and the Pittsburgh Sleep Quality Index [PSQI], respectively. RESULTS: A total of 544 consecutive adult IBD patients were included [50% women, mean age 44 years, 61% Crohn's disease]. The prevalence of fatigue was 41% (95% confidence interval [CI] = 37-45%). The variables associated with an increased risk of fatigue were: anxiety [OR = 2.5, 95% CI = 1.6-3.7], depression [OR = 2.4, 95% CI = 1.4-3.8], presence of extraintestinal manifestations [EIMs] [OR = 1.7, 95% CI = 1.1-2.6], and treatment with systemic steroids [OR = 2.8, 95% CI = 1.4-5.7]. The presence of EIMs [regression coefficient, RC = 8.2, 95% CI = 2.3-14.2], anxiety [RC = 25.8, 95% CI = 20.0-31.5], depression [RC = 30.6, 95% CI = 24.3-37.0], and sleep disturbances [RC = 15.0, 95% CI = 9.3-20.8] were associated with severity of fatigue. Patients with fatigue had a significantly decreased IBDQ-9 score [p < 0.001]. CONCLUSIONS: The prevalence of fatigue in IBD patients is remarkably high and has a negative impact on QoL. Therapy with systemic steroids is associated with an increased risk of fatigue. The severity of fatigue is associated with anxiety, depression, sleep disorders, and the presence of EIMs. Fatigue was not associated with anaemia, disease activity or anti-TNF therapy.

Mechanical deformation inhibits IL-10 and stimulates IL-12 production by mouse calvarial osteoblasts in vitro.

The skeleton is continuously remodelled throughout life, a process that is orchestrated by cells of the osteoblast lineage. Remodelling involves a complex network of cell-cell signalling involving systemic hormones, locally produced cytokines, growth factors and the mechanical environment of the cells. Here, we report on the effect of mechanically-induced strain on the synthesis by mouse calvarial osteoblasts in monolayer culture of IL-10 and IL-12, two cytokines that inhibit osteoclast formation in bone marrow cultures; IL-10 also suppresses osteoblast differentiation suggesting a role for both cytokines in bone physiology. A tensile strain was applied to the cells intermittently for 6s, every 90s, for 2-96h. After 2-h culture, supernatants from deformed cells contained significantly less IL-10 than control cultures. In contrast, mechanical deformation had a stimulatory effect on IL-12 synthesis; however, by 48h both had returned to control levels. These data suggest that IL-10 and IL-12 can be added to the growing list of mechanical stress-responsive genes. The down-regulation of IL-10 and stimulation of IL-12 further suggests that the initial response of the cells to mechanical deformation was an osteogenic one.

Cyclosporine in the treatment of severe attack of ulcerative colitis: a systematic review.

INTRODUCTION: Intravenous steroid therapy is the standard treatment in severe attacks of ulcerative colitis (UC), but 20% to 60% of patients fail to respond and require colectomy. Cyclosporine (CyA) has shown efficacy in steroid failures and could avoid surgery, but controversy remains. AIM: The objective of this study was to conduct a systematic review to evaluate the effectiveness and safety of CyA in inducing remission in patients with a severe attack of UC. METHODS: We did a systematic review using Cochrane methodology, including data from published (in English, French, Spanish or German) clinical trials done in adults using intravenous or oral CyA in UC. Data on efficacy are obtained from controlled and observational clinical trials, and for safety issues case reports are also considered. RESULTS: 31 studies were identified which met the inclusion criteria, 22 (18 uncontrolled, 4 controlled) with intravenous CyA, and 9 (all uncontrolled) using oral CyA. Only 4 controlled trials (one in abstract form) are available, and only one compares CyA to placebo. However, efficacy results are very consistent in these 4 trials, and very similar to those in observational studies. CyA achieves remission in 91,4% and 71.4% of patients in controlled and uncontrolled studies using intravenous route, and in 71,2% using oral route. Two mg/kg/day seems so efficacious and safer as previous standard 4 mg/kg/day dose. Minor side effects are rather common but do not seriously limit therapy. Severe side effects, specially infections, are uncommon but clinically relevant with several deaths reported. CONCLUSION: CyA (intravenous, 2 mg/kg/day) constitutes an efficacious and relatively safe alternative in the treatment of severe, steroid-refractory, attack of UC. To optimize treatment, the correct selection of patients, a standardized protocol and clinical surveillance are recommended.

[Hypothyroidism as a complication of the treatment of hepatitis C with interferon]. / Hipotiroidismo como complicación del tratamiento con interferón de la hepatitis C.

Interferon is becoming the most important therapy for chronic hepatitis due to hepatitis C virus. Secondary effects are frequent and sometimes so important to stop the therapy. Autoimmune disorders, specially autoimmune thyroid diseases may occur. We report two out of 69 chronic hepatitis C patients treated with interferon who developed hypothyroidism, that required definitive substitutive therapy.

Therapeutic guidelines on ulcerative colitis: a GRADE methodology based effort of GETECCU / Guía clínica GETECCU del tratamiento de la colitis ulcerosa elaborada con la metodología GRADE

Los objetivos de la Guía son: 1. Establecer recomendaciones basadas en las pruebas disponibles, para el tratamiento de inducción en el brote grave de colitis ulcerativa 2. Establecer recomendaciones para el tratamiento de inducción en el brote leve- moderado de colitis ulcerativa 3. Establecer recomendaciones para el tratamiento de mantenimiento de la colitis ulcerativa en remisión

[Changes in dental caries indexes in school children in an area of Xochimilco, Mexico: 1984-1992]. / Cambios en los índices de caries dental en escolares de una zona de Xochimilco, México: 1984-1992.

OBJECTIVE: To describe the changes in dental caries prevalence and severity, in a group of primary schoolchildren. Two dental caries surveys were carried out, one in 1984 and the other in 1992. MATERIAL AND METHODS: The dental caries indices were registered using the World Health Organization's criteria. A group of 6-7 years old schoolchildren living in the East Region of Xochimilco were included in the study. A total of 279 children participated in this study; 153 in 1984 and 126 in 1992. RESULTS: The mean value of the deft index was 5.65 (SD 3.35) in 1984, and the mean value of the deft index was 4.89 (SD 3.7) in 1992. For the permanent dentition the DMFT was 0.51 (SD 1.0) in 1984 and 0.48 (SD 0.82) in 1992. Differences in dental caries indices, between the first and second survey, were significant only for the primary dentition in the six years old group (95% CI 0.36, 2.15). An increase in the proportion of filled teeth was found. However, the treatment needs are still very high (69% for primary teeth and 86% for permanent teeth). CONCLUSIONS: The findings from this study seem to indicate little change in the prevalence and severity of dental caries in the population in the period of study.

Cyclosporine in the treatment of severe attack of ulcerative colitis: a systematic review

Introducción: La administración intravenosa de esteroides es el tratamiento habitual en los episodios graves de colitis ulcerosa (CU), aunque el 20-60% de los pacientes no responde a él y precisa intervención quirúrgica mediante colectomía. La ciclosporina (CyA) ha demostrado ser eficaz en los cuadros de falta de respuesta a los esteroides y podría evitar la intervención quirúrgica; no obstante, existe controversia a este respecto. Objetivo: El objetivo del presente estudio ha sido efectuar una revisión sistemática con objeto de evaluar la eficacia y seguridad de la CyA para conseguir la remisión en pacientes con un episodio grave de CU. Métodos: Revisión sistemática mediante la metodología Cochrane, incluyendo los datos correspondientes a los ensayos clínicos publicados en inglés, francés, español o alemán, y referidos a pacientes adultos con CU tratados mediante la administración intravenosa u oral de CyA. Los datos de eficacia se obtuvieron a partir de los ensayos clínicos efectuados con controles y de los estudios de observación; también se consideraron los casos aislados respecto a las cuestiones de seguridad. Resultados: Se identificaron 31 estudios que cumplían los criterios de inclusión en la revisión, 22 (18 sin control y 4 con control) en los que se administró CyA intravenosa y 9 (todos ellos sin grupo control) en los que se administró CyA por vía oral. Sólo se hallaron 4 ensayos clínicos realizados con controles (uno de ellos publicado en forma de resumen), y en sólo uno de ellos se comparó la CyA con placebo. No obstante, los resultados de eficacia fueron muy similares en los 4 ensayos clínicos y también en los estudios de observación. En los estudios realizados con y sin controles, la CyA intravenosa dio lugar a remisión en el 91,4 y el 71,4% de los pacientes, respectivamente, mientras que el porcentaje correspondiente a la CyA oral fue del 71,2%. La dosis de 2 mg/kg/día pareció tener una eficacia y una seguridad similares a las de la dosis habitual utilizada previamente, de 4 mg/kg/día. Los efectos adversos de carácter menor fueron bastante frecuentes, pero no limitaron gravemente el tratamiento. Los efectos adversos graves, en especial las infecciones, fueron infrecuentes pero potencialmente graves; en los estudios publicados se produjeron varios fallecimientos por esta causa. Conclusión: La CyA intravenosa en dosis de 2 mg/kg/día constituye una opción eficaz y relativamente segura en el tratamiento de los episodios graves de CU refractarios a los esteroides. Para optimizar el tratamiento, se recomiendan una selección correcta de los pacientes y la aplicación de un protocolo estandarizado de tratamiento y de seguimiento clínico

Introduction: Intravenous steroid therapy is the standard treatment in severe attacks of ulcerative colitis (UC), but 20% to 60% of patients fail to respond and require colectomy. Cyclosporine (CyA) has shown efficacy in steroid failures and could avoid surgery, but controversy remains. Aim: The objective of this study was to conduct a systematic review to evaluate the effectiveness and safety of CyA in inducing remission in patients with a severe attack of UC. Methods: We did a systematic review using Cochrane methodology, including data from published (in English, French, Spanish or German) clinical trials done in adults using intravenous or oral CyA in UC. Data on efficacy are obtained from controlled and observational clinical trials, and for safety issues case reports are also considered. Results: 31 studies were identified which met the inclusion criteria, 22 (18 uncontrolled, 4 controlled) with intravenous CyA, and 9 (all uncontrolled) using oral CyA. Only 4 controlled trials (one in abstract form) are available, and only one compares CyA to placebo. However, efficacy results are very consistent in these 4 trials, and very similar to those in observational studies. CyA achieves remission in 91,4% and 71.4% of patients in controlled and uncontrolled studies using intravenous route, and in 71,2% using oral route. Two mg/kg/day seems so efficacious and safer as previous standard 4 mg/kg/day dose. Minor side effects are rather common but do not seriously limit therapy. Severe side effects, specially infections, are uncommon but clinically relevant with several deaths reported. Conclusion: CyA (intravenous, 2 mg/kg/day) constitutes an efficacious and relatively safe alternative in the treatment of severe, steroid-refractory, attack of UC. To optimize treatment, the correct selection of patients, a standardized protocol and clinical surveillance are recommended