Víctor Manuel Navas-López

Efficacy and safety of adalimumab in the treatment of Crohn's disease in children

OBJECTIVES to describe the efficacy and safety of adalimumab (ADA) in inducing clinical remission and reducing inflammation of intestinal mucosa in children with Crohn´s disease (CD). METHODS we carried out a descriptive, observational study with all patients diagnosed with CD and treated with ADA between January 2007 and March 2013. Disease activity was determined using the Pediatric Crohn´s Disease Activity Index (PCDAI), and the degree of mucosa inflammation by fecal calprotectin (FC). RESULTS sixteen patients were included. Mean age at diagnosis was 10.6 ± 2.5 years, with a mean age at start of ADA treatment of 12.4 ± 1.8 years, and a median of 1.4 years (IQR 0.5-3) duration from CD diagnosis to start of treatment. Twelve patients were naïve to anti-TNF-a. The PCDAI score at start of ADA treatment was significantly reduced at 12 weeks of follow-up (31.25 IQR 26.8-37.5 vs. 1.2 IQR 0.0-5.0; p = 0.001). Similarly, the FC level decreased at 12 weeks (749 μg/g IQR 514-898 vs. 126 μg/g IQR 67.7-239.2; p = 0.02). Surgery was performed in 4 patients. Adverse events were reported in 4 patients. One patient developed lymphoma at 4 years of ADA treatment in monotherapy. CONCLUSIONS ADA has been shown to be effective in children with moderate-to-severe CD. Treatment benefits should be weighed against side effects. Multicenter longitudinal studies with longer follow-up periods are required to determine the true efficacy and safety of long-term ADA treatment.

Oral tacrolimus for pediatric steroid-resistant ulcerative colitis

BACKGROUND Ulcerative colitis (UC) occurring during childhood is generally extensive and is associated with severe flares that may require intravenous steroid treatment. In cases of corticosteroid resistance is necessary to introduce a second-line treatment to avoid or delay surgery. AIMS To describe the efficacy and safety of oral tacrolimus for the treatment of severe steroid-resistant UC. METHODS We performed a retrospective study that included all patients under age 18 suffering from severe steroid-resistant UC treated with oral tacrolimus during the period January 1998 to October 2012 and with a follow-up period after treatment of 24 months or more. RESULTS A total of ten patients were included. The age at baseline was 9.4±4.9 years, and the time from diagnosis was 1.3 months (IQR, 1-5.7). Seven of the patients were in their first flare of disease. All of them received an oral dose of 0.12 mg/kg/day of tacrolimus divided in two doses. Trough plasma levels of tacrolimus were maintained between 4 and 13 ng/ml. Response was seen in 5/10 patients at 12 months, colectomy was eventually performed in 60% of patients during the follow-up period. CONCLUSIONS Tacrolimus is useful in inducing remission in patients with severe steroid-resistant UC, preventing or delaying colectomy, and allowing the patient and family to prepare for a probable surgery. Tacrolimus may also be used as a treatment bridge for corticosteroid-dependent patients until the new maintenance therapy takes effect.

La nutrición enteral exclusiva continua siendo el tratamiento de primera línea en la enfermedad de Crohn pediátrica en la era de los biológicos

INTRODUCTION Exclusive enteral nutrition (EEN) has been to be more effective than corticosteroids in achieving mucosal healing without their side effects. OBJECTIVES To determine the efficacy of EEN in terms of inducing clinical remission in newly diagnosed CD children and to study the efficacy of this therapeutic approach in improving the degree of intestinal mucosa inflammation. MATERIALS AND METHODS The medical records of patients with newly diagnosed Crohns disease treated with EEN were reviewed retrospectively. The degree of mucosal inflammation was assessed by fecal calprotectin (FC). Remission was defined as a PCDAI<10. RESULTS Forty patients (24 males) were included, the age at diagnosis was 11.6 ± 3.6 years. Of the 34 patients who completed the EEN period, 32 (94% per-protocol analysis) achieved clinical remission. This percentage fell to 80% in the intention-to-treat analysis. The compliance rate was 95%. Duration of EEN was 6.42 weeks (IQR 6.0-8.14). FC was significantly higher in patients with moderate and severe disease. Median baseline FC levels (680 μg/g) decreased significantly to 218 μg/g (P<0.0001) after EEN. We found a statistically significant correlation between FC and PCDAI (rho=0.727; P<0.0001). Early use of thiopurines (< 8 weeks) versus subsequent use was not associated with improved outcomes during the follow-up. CONCLUSIONS EEN administered for 6-8 weeks is effective for inducing clinical remission and decreasing the degree of mucosal inflammation. We did not find differences in terms of maintenance of remission in patients treated early with thiopurines.

Successful Mercaptopurine Usage Despite Azathioprine-Induced Pancreatitis in Paediatric Crohn's Disease

BACKGROUND Azathioprine [AZA] and mercaptopurine [MP] are recommended for maintenance of steroid-free remission in children with Crohn`s disease [CD]. Azathioprine-induced pancreatitis, an idiosyncratic and major side effect, has been considered as an absolute contraindication for the use of a second thiopurine in IBD patients. MATERIALS AND METHODS We describe two children with CD in whom MP were successfully trialled after a confirmed azathioprine-induced pancreatitis, being well tolerated in both cases. RESULTS Two boys [13 and 10 years old] started exclusive enteral nutrition after diagnosis of moderate (Pediatric Crohns Disease Activity Index [wPCDAI] = 45) and mild [wPCDAI = 35] CD. Both developed an acute mild to moderate pancreatitis after 2 and 3 weeks, respectively, of AZA treatment but recovered fully in hospital after AZA withdrawal. They started on MP treatment without any adverse effect. They were tested for the presence of polymorphisms 238G>C, 460G>A, and 719A>G in the TPMT gene and 94C>A and 21>C in the ITPase. Both patients were wild-type for all tested polymorphisms. CONCLUSIONS Azathioprine-induced acute pancreatitis should not be considered as an absolute contraindication for the use of MP. Further investigation is required to create a better understanding of the mechanism underlying the adverse events and to allow more possibilities for personalised therapy.

PRESENT; PREScription of Enteral Nutrition in pediaTric Crohn´s disease in Spain

OBJECTIVES Exclusive enteral nutrition (EEN) is one of the therapeutic strategies used to induce remission in pediatric Crohns disease (CD). Although its use is recommended in clinical practice guidelines and consensus documents, the frequency of this practice in Spain is unknown. METHODS A 70-item questionnaire ( PRESENT PREScription of Enteral Nutrition in pediaTric Crohns disease in Spain) was drafted and distributed through the SEGHNP (Spanish Society for Pediatric Gastroenterology, Hepatology and Nutrition) e-mail list. RESULTS We received information from 51 Pediatric Gastroenterology Units. Of the 287 patients newly diagnosed with CD in 2011-2012 at these centres (139 in 2011, 148 in 2012), 182 (63%) received EEN (58% in 2011 and 68% in 2012). 26% of the patients who received EEN in the period studied (64/246) did so during relapses. All the physicians (100%) who responded to the questionnaire believe that EEN is effective in inducing clinical remission in mild to moderate CD. However, 24.5% of respondents never use EEN during relapses. The enteral formulas used most often used were polymeric formulas specific for CD (70.6%) and the preferred administration route was oral, with 60.8% using flavouring and 9.3% allowing a variable percentage of calories in the form of other foods. 65% use 5-ASA together with EEN, 69% use antibiotics and 95% immunomodulators (thiopurines). The duration of EEN tends to be 8 weeks (47.1%), and transition to regular diet was achieved sequentially over a variable period of time. Regarding barriers and limiting factors for the use of EEN, those most frequently reported include lack of acceptance by the patient and/or family (71%), lack of time and/or ancillary staff (69%) and difficulty in convincing the patient and/or family of the suitability of treatment (43%). CONCLUSIONS EEN use rates are similar to those of other European questionnaires. Tools that facilitate acceptance by the patient and family are needed. Increasing the time dedicated to this therapeutic modality is likewise important. Given the disparity of criteria for indicating treatment with EEN, it would be useful to have widely accepted clinical practice guidelines or protocols that facilitate the decision to use it.

La composición de la microbiota duodenal en niños con enfermedad celíaca activa está influenciada por el grado de enteropatía

OBJECTIVES To establish whether the duodenal mucosa microbiota of children with active coeliac disease (CD) and healthy controls (HC) differ in composition and biodiversity. MATERIAL AND METHODS Samples of duodenal biopsies in 11 CD patients were obtained at diagnosis, and in 6 HC who were investigated for functional intestinal disorders of non-CD origin. Total duodenal microbiota and the belonging to the genus Lactobacillus using PCR-denaturing gradient gel electrophoresis (DGGE) were analysed. The banding patterns obtained in the resulting gels were analysed to determine the differences between the microbiota of CD patients and HC (FPQuest 4.5) while environmental indexes (richness, diversity and habitability) were calculated with the Past version 2.17 program. RESULTS The intestinal microbiota of patients with Marsh 3c lesion showed similarity of 98% and differs from other CD patients with other type of histologic lesion as Marsh3a, Marsh3b and Marsh2. The main differences were obtained in ecological indexes belonging to the genus Lactobacillus, with significant richness, diversity and habitability reduction in CD patients. In CD bands were categorized primarily with Streptococcus, Bacteroides and E.coli species. In HC the predominant bands were Bifidobacterium, Lactobacillus and Acinetobacter, though the Streptococcus and Bacteroides were lower. CONCLUSIONS The celiac patients with major histological affectation presented a similar microbiota duodenal. The ecological indexes applied to the genus Lactobacillus were significantly reduced in CD.

Pancreatic Involvement in Pediatric Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic condition that includes two clinical entities: Crohn’s disease and ulcerative colitis. Although both entities mainly affect the gastrointestinal tract are considered multisystemic diseases and may present extraintestinal manifestations involving other organs and systems. Pancreatic involvement in Pediatric IBD includes a heterogeneous group of clinical entities like acute pancreatitis, chronic pancreatitis, autoimmune pancreatitis, asymptomatic exocrine pancreatic insufficiency, increased pancreatic enzyme levels, structural abnormalities, and granulomatous inflammation. Although the mechanism for pancreatic involvement in IBD is not clearly elucidated, is important to keep in mind the association of these two entities in order to perform a prompt diagnosis and establish an appropriate treatment. The objective of this review is to update the available evidence on pancreatic involvement in children with IBD.

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Abstract Background and Aims An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. Methods A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. Results Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. Conclusions Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

Efectividad y seguridad en nuestro entorno de adalimumab como tratamiento anti-TNF de primera linea en niños con enfermedad de Crohn

BACKGROUND AND OBJECTIVES Adalimumab (ADA), a monoclonal humanised anti-TNF antibody, is usually prescribed as a second-line treatment in paediatric Crohns disease (CD) patients who have become unresponsive or developed intolerance to infliximab (IFX). In the case series reported, more than 70% of patients had initially been treated with IFX. Data on short- and long-term effectiveness of ADA in anti-TNF naïve patients is limited. The aim of this study is to describe our experience with ADA as a first-line anti-TNF in paediatric CD patients. MATERIAL AND METHODS This is a multicentre retrospective study including anti-TNF naïve paediatric CD patients treated with ADA as first-line anti-TNF. RESULTS Sixty-two patients (34males), with a mean age of 13.0±2.4years and a disease duration of 7.3 (IQR 2.7-21) months were included. Median wPCDAI was 35 (IQR 24.3-47.5). Fifty-eight out of 62 (93.5%) were on combo therapy at baseline. Clinical remission at week12 was achieved in 50 out of 62 (80.6%) and in 57 out of 60 (95.0%) at week52. Eight patients (13%) reported adverse events. Mean height, growth rate and BMI z-scores improved significantly between baseline and week 52, especially in patients with growth failure. CONCLUSIONS ADA treatment leads to lasting clinical remission in anti-TNF naïve paediatric patients with CD. ADA significantly improved growth rate in children with CD who had growth delay at baseline.

Trasplante de microbiota fecal en niño con enfermedad inflamatoria intestinal de inicio muy precoz

1. Venema W, Voskuil M, Dijkstra G, Weersma R, Festen E. The genetic background of inflammatory bowel disease: from correlation to causality. J Pathol. 2017;241:146--58. 2. Kammermeier J, Dziubak R, Pescarin M, Drury S, Godwin H, Reeve K, et al. Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years. J Crohns Colitis. 2017;11:60--9. 3. Maaser C, Langholz E, Gordon A, Burisch J, Ellul P, Hernández V, et al. European Crohn’s and colitis organisation topical review on environmental factors in IBD. J Crohns Colitis. 2017;11:905--20. 4. Prosberg M, Bentsen F, Vind I, Petersen AM, Gluud LL. The association between the gut microbiota and the inflammatory bowel disease activity: a systematic review and meta-analysis. Scand J Gastroenterol. 2016;51:1407--15. 5. Martín de Carpi J, Rodríguez A, Ramos E, Jiménez S, Martínez-Gómez MJ, Medina E. Increasing incidence of pediatric inflammatory bowel disease in Spain (1996--2009): the SPIRIT Registry. Inflamm Bowel Dis. 2013;19:73--80. 6. Torki M, Gholamrezaei A, Mirbagher L, Danesh M, Kheiri S, Emami M. Vitamin D deficiency associated with disease activity in patients with inflammatory bowel diseases. Dig Dis Sci. 2015;60:3085--91.