Controversies in the management of anti-TNF therapy in patients with Crohn's disease: a Delphi consensus.

BACKGROUND: Despite research, there are still controversial areas in the management of Crohn's disease (CD). OBJECTIVE: To establish practical recommendations on using anti-tumour necrosis factor (TNF) drugs in patients with moderate-to-severe CD. METHODS: Clinical controversies in the management of CD using anti-TNF therapies were identified. A comprehensive literature review was performed, and a national survey was launched to examine current clinical practices when using anti-TNF therapies. Their results were discussed by expert gastroenterologists within a nominal group meeting, and a set of statements was proposed and tested in a Delphi process. RESULTS: Qualitative study. The survey and Delphi process were sent to 244 CD-treating physicians (response rate: 58%). A total of 14 statements were generated. All but two achieved agreement. These statements cover: (1) use of first-line non-anti-TNF biological therapy; (2) role of HLA-DQA1*05 in daily practice; (3) attitudes in primary non-response and loss of response to anti-TNF therapy due to immunogenicity; (4) use of ustekinumab or vedolizumab if a change in action mechanism is warranted; (5) anti-TNF drug level monitoring; (6) combined therapy with an immunomodulator. CONCLUSION: This document sought to pull together the best evidence, experts' opinions, and treating physicians' attitudes when using anti-TNF therapies in patients with CD.

Association between HLA DNA Variants and Long-Term Response to Anti-TNF Drugs in a Spanish Pediatric Inflammatory Bowel Disease Cohort.

The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.

Management and Long-term Outcomes of Crohn's Disease Complicated with Enterocutaneous Fistula: ECUFIT Study from GETECCU.

BACKGROUND AND AIMS: Crohn's disease [CD] can develop penetrating complications at any time during the disease course. Enterocutaneous fistulae [ECF] are disease-related complications with an important impact on quality of life. Our aim was to describe the outcomes of this complication, including its medical and/or surgical management and their temporal trends. The primary endpoint was fistula closure, defined as the absence of drainage, with no new abscess or surgery, over the preceding 6 months. METHODS: Clinical information from all adult patients with CD and at least one ECF-excluding perianal fistulae-were identified from the prospectively-maintained ENEIDA registry. All additional information regarding treatment for this complication was retrospectively reviewed. RESULTS: A total of 301 ECF in 286 patients [January 1970-September 2020] were analysed out of 30 088 records. These lesions were mostly located in the ileum [67%] and they had a median of one external opening [range 1-10]. After a median follow-up of 146 months (interquartile range [IQR], 69-233), 69% of patients underwent surgery. Fistula closure was achieved in 84%, mostly after surgery, and fistula recurrence was uncommon [13%]. Spontaneous and low-output fistulae were associated with higher closure rates (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.17-1.93, p = 0.001, and HR 1.49, 95% CI 1.07-2.06, p = 0.03, respectively); this was obtained more frequently with medical therapy since biologics have been available. CONCLUSIONS: ECF complicating CD are rare but entail a high burden of medical and surgical resources. Closure rates are high, usually after surgery, and fistula recurrence is uncommon. A significant proportion of patients receiving medical therapy can achieve fistula closure.

Immigrant IBD Patients in Spain Are Younger, Have More Extraintestinal Manifestations and Use More Biologics Than Native Patients.

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.

Rapidity of clinical response to adalimumab and improvement of quality of life in luminal Crohn's disease: RAPIDA study.

OBJECTIVE: No studies evaluating the rapidity of response to biological therapies are available for Crohn's disease (CD). The aim of this study was to evaluate rapidity of onset of clinical response and impact on quality of life (QoL) of adalimumab therapy in adult anti-TNF-naïve patients with moderately-to-severely active CD. PATIENTS AND METHODS: RAPIDA was an open-label, single-arm, prospective, multicenter clinical trial. Adult patients with moderately-to-severely active luminal CD, anti-TNF-naïve, and unresponsive to conventional therapy were treated with adalimumab. Clinical disease activity, QoL and inflammatory biomarkers were measured at day 4, and weeks 1, 2, 4, and 12 after treatment initiation. RESULTS: Eighty-six patients were included in the intention-to-treat (ITT) analyses. Clinical disease activity was reduced from a median of 9.0 points to 6.0 points at day 4. Clinical response (≥ 3-point reduction in the Harvey-Bradshaw Index, HBI) was achieved by 61.6% (d4) and 75.6% (w1) of patients in the ITT population (median 2.5 days) and with non-responder imputation (NRI), by 55.8% and 53.4%, respectively. The proportion of patients in clinical remission (HBI<5) at weeks 2 and 4 in the ITT population was 54.7% and 62.8%, respectively (median 7.0 days), and 38.4% and 45.3% in the NRI population. All QoL scores significantly improved and inflammatory biomarkers significantly decreased from day 4 onwards (p<0.0001). CONCLUSION: Rapid clinical response and remission, improvement in QoL and fatigue, and a reduction of inflammatory biomarkers were achieved with adalimumab as early as day 4 in adult anti-TNF-naïve patients with moderately-to-severely active CD.

Relationship between IGF-1 and body weight in inflammatory bowel diseases: Cellular and molecular mechanisms involved.

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic inflammation of the gastrointestinal tract, what leads to diarrhea, malnutrition, and weight loss. Depression of the growth hormone-insulin-like growth factor-1 axis (GH-IGF-1 axis) could be responsible of these symptoms. We demonstrate that long-term treatment (54 weeks) of adult CD patients with adalimumab (ADA) results in a decrease in serum IGF-1 without changes in serum IGF-1 binding protein (IGF1BP4). These results prompted us to conduct a preclinical study to test the efficiency of IGF-1 in the medication for experimental colitis. IGF-1 treatment of rats with DSS-induced colitis has a beneficial effect on the following circulating biochemical parameters: glucose, albumin, and total protein levels. In this experimental group we also observed healthy maintenance of colon size, body weight, and lean mass in comparison with the DSS-only group. Histological analysis revealed restoration of the mucosal barrier with the IGF-1 treatment, which was characterized by healthy quantities of mucin production, structural maintenance of adherers junctions (AJs), recuperation of E-cadherin and ß-catenin levels and decrease in infiltrating immune cells and in metalloproteinase-2 levels. The experimentally induced colitis caused activation of apoptosis markers, including cleaved caspase 3, caspase 8, and PARP and decreases cell-cycle checkpoint activators including phosphorylated Rb, cyclin E, and E2F1. The IGF-1 treatment inhibited cyclin E depletion and partially protects PARP levels. The beneficial effects of IGF-1 in experimental colitis could be explained by a re-sensitization of the IGF-1/IRS-1/AKT cascade to exogenous IGF-1. Given these results, we postulate that IGF-1 treatment of IBD patients could prove to be successful in reducing disease pathology.

Histological inflammatory activity can predict endoscopic relapse in patients with ulcerative colitis who have achieved mucosal healing.

BACKGROUND AIMS: Current therapeutic goals in ulcerative colitis (UC) include clinical and endoscopic remission, named mucosal healing (MH). Despite MH, a proportion of patients suffer a clinical relapse, which has been related to histological inflammation. We aimed to identify which histopathological features or histopathological index cut-off was associated with endoscopic relapse (ER) in UC patients with MH. METHODS: Retrospective analysis of UC patients who underwent surveillance colonoscopy showing complete MH (endoscopic Mayo subscore=0) with random biopsies, and at least one more endoscopy along the follow-up. After a consensus meeting, expert pathologist performed histological assessment according to Simplified Geboes Score (SGS), Nancy Index (NI) and Robarts Histopathological Index (RHI). Other histopathological features were also evaluated. Patients were followed until ER or last endoscopy performed showing persistence of MH. RESULTS: A total of 95 patients (150 colonoscopies) were included. After mean follow-up of 31.2 months (SD 21.7), 33 patients (34.7%) suffered ER. Neutrophils in lamina propria (OR 2.6; P = 0.037), within the epithelium (OR 2.6; P = 0.03), SGS ≥3.1 (OR 2.6; P = 0.037), NI ≥2 (OR 2.6; P = 0.03) and RHI ≥5 (OR 2.6; P = 0.037) were associated with ER in univariate analysis. In multivariate analysis, eosinophils in the lamina propria (HR 2.5; P = 0.01) and clinical remission<12 months (HR 3.2; P = 0.002) were associated with ER. CONCLUSIONS: Histopathological findings in UC patients who have achieved endoscopic MH may predict ER. Standardized histopathology reports according to the presence of neutrophils, eosinophils or to defined cut-off of validated histopathologic indexes may represent a useful tool to predict ER and should be considered at therapeutic and surveillance decision process.

Comparison of a new rapid method for determination of serum anti-adalimumab and anti-infliximab antibodies with two established ELISA kits.

BACKGROUND: Adalimumab (ADL), infliximab (IFX) and their biosimilars are widely used biological drugs. Some patients, however, generate neutralizing antibodies that hamper the effectiveness of these drugs. Evidence shows therapeutic drug monitoring of serum levels ADL/IFX and anti-drug antibodies (ADA) is useful to improve treatment effectiveness. We evaluated a new rapid quantitative method, Quantum Blue (QB), for determining serum anti-ADL and anti-IFX antibodies (Research Use Only labelling) by comparing it with two established ELISA kits, Promonitor (PM) and Lisa-Tracker (LT). METHODS: Eighty samples (40 for each drug type) were analysed. Percentage of agreement and kappa statistic were used to compare positive/negative ADA results. Clinical implications for drug treatment in the patients with discordant results were evaluated. The Chi-square test was used to analyze differences for ADA detection in patients with disease flare and without concomitant immunosuppressant treatment. RESULTS: Agreement exceeded 80 % among anti-ADL methods. Although LT ELISA showed a lower capacity in detecting anti-ADL antibodies, discrepancies were found for levels close to the cut-off concentration, thus having minimal impact on clinical decisions. Conversely, QB anti-IFX displayed low agreement with PM and LT ELISA kits (67.5 % and 50 %, respectively), and was unable to detect high levels of antibodies, therefore having major clinical implications. Agreement between PM and LT ELISA anti-IFX kits was 82.5 % with all discordant results being undetected for PM and slightly positive for LT. CONCLUSION: QB anti-ADL shows similar performance to ELISA kits while QB anti-IFX needs further improvements to achieve reliable antibody detection.

Comparison of original and biosimilar infliximab (CTP-13) in biologic-naïve patients with Crohn's disease and ulcerative colitis: a retrospective, multicenter real-life study in Spain.

PURPOSE: biosimilar infliximab (CTP-13) has been recently approved for the treatment of several immune-mediated inflammatory disorders, including inflammatory bowel disease (IBD). Comparative studies between this biosimilar and original infliximab in the real clinical practice are scarce. The objective of this study was to compare short and long-term safety and efficacy of original (O) and biosimilar infliximab (B-IFX) in biologic-naïve, IBD patients in the real life clinical practice. METHODS: a retrospective, multicentric study was performed in five Spanish hospitals. Consecutive IBD, biologic-naïve patients from an historic cohort who initiated O-IFX from January 2013 were compared with biologic-naïve patients, who started treatment with B-IFX since its approval in January 2015. The evaluation of efficacy was assessed after the induction phase, at week 14 and week 54 of treatment. Time to dose escalation or treatment persistence of both O-IFX and B-IFX was also considered. The appearance of serious adverse events was recorded. RESULTS: two hundred and thirty-nine IBD biologic-naïve patients who started with O-IFX or B-IFX were included: 153 patients were diagnosed with Crohn's disease (95 treated with O- and 58 treated with B-IFX) and 86 with ulcerative colitis (40 received O- and 46 received B-IFX). At weeks 14 and 54, both O-IFX and B-IFX groups reached a similar clinical response and remission rates. Time to dose escalation, treatment persistence and safety profile were comparable between both groups. CONCLUSIONS: this long-term real-life experience provides additional evidence of the similarity of O- and B-IFX CTP-13 in terms of efficacy and safety in IBD patients.

Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on pouchitis in ulcerative colitis. Part 2: Treatment. / Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) sobre la reservoritis en la colitis ulcerosa. Parte 2: Tratamiento.

Pouchitis treatment is a complex entity that requires a close medical and surgical relationship. The elective treatment for acute pouchitis is antibiotics. After a first episode of pouchitis it is recommended prophylaxis therapy with a probiotic mix, nevertheless it is not clear the use of this formulation for preventing a first episode of pouchitis after surgery. First-line treatment for chronic pouchitis is an antibiotic combination. The next step in treatment should be oral budesonide. Selected cases of severe, chronic refractory pouchitis may benefit from biologic agents, and anti-TNF α should be recommended as the first option, leaving the new biologicals for multi-refractory patients. Permanent ileostomy may be an option in severe refractory cases to medical treatment.

COVID-19 and inflammatory bowel disease: questions arising from patient care and follow-up during the initial phase of the pandemic (February-April 2020). / COVID-19 y enfermedad inflamatoria intestinal: preguntas surgidas de la atención y seguimiento de los pacientes durante la fase inicial de la pandemia (febrero-abril 2020).

COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was described in China in late 2019. There are currently more than three million diagnosed cases, constituting a pandemic which has caused a worldwide crisis. The devastating effects of this infection are due to its highly contagious nature and although mild forms predominate, in absolute values, the rates for severe forms and mortality are very high. The information on the characteristics of the infection in inflammatory bowel disease is of special interest, as these patients have higher attendance at health centres, which may increase their risk of infection. Furthermore, the treatments used to control the inflammatory activity may modify the disease course of COVID-19. The Spanish Working Group on Crohn's Disease and Ulcerative Colitis and the Spanish Nurses Working Group on Inflammatory Bowel Disease have prepared this document as a practical response to some common questions about the treatment of these patients.

Impact of comorbidities on anti-TNFα response and relapse in patients with inflammatory bowel disease: the VERNE study.

Objective: To evaluate the impact of comorbidities and extraintestinal manifestations of inflammatory bowel disease on the response of patients with inflammatory bowel disease to antitumour necrosis factor alpha (anti-TNFα) therapy. Design: Data from 310 patients (194 with Crohn's disease and 116 with ulcerative colitis) treated consecutively with the first anti-TNFα in 24 Spanish hospitals were retrospectively analysed. Univariate and multivariate logistic regression analyses were performed to assess the associations between inflammatory bowel disease comorbidities and extraintestinal manifestations with anti-TNFα treatment outcomes. Key clinical features, such as type of inflammatory bowel disease and concomitant treatments, were included as fixed factors in the model. Results: Multivariate logistic regression analyses (OR, 95% CI) showed that chronic obstructive pulmonary disease (2.67, 1.33 to 5.35) and hepato-pancreato-biliary diseases (1.87, 1.48 to 2.36) were significantly associated with primary non-response to anti-TNFα, as was the use of corticosteroids and the type of inflammatory bowel disease (ulcerative colitis vs Crohn's disease). It was also found that myocardial infarction (3.30, 1.48 to 7.35) and skin disease (2.73, 1.42 to 5.25) were significantly associated with loss of response, along with the use of corticosteroids and the type of inflammatory bowel disease (ulcerative colitis vs Crohn's disease). Conclusions: Our results suggest that the presence of some comorbidities in patients with inflammatory bowel disease, such as chronic obstructive pulmonary disease and myocardial infarction, and of certain extraintestinal manifestations of inflammatory bowel disease, such as hepato-pancreato-biliary conditions and skin diseases, appear to be related to failure to anti-TNFα treatment. Therefore, their presence should be considered when choosing a treatment. Trial registration number: NCT02861118.

Usefulness of monitoring antitumor necrosis factor serum levels during the induction phase in patients with Crohn's disease.

AIMS: The aims of this study were (a) to know the kinetics of antitumor necrosis factor (TNF) drug serum levels during the induction phase in patients with Crohn's disease; (b) to identify variables associated with these levels; and (c) to assess the relation between these levels and short-term effectiveness in Crohn's disease patients. METHODS: Patients with Crohn's disease naïve to anti-TNF treatment were prospectively included. Remission was defined as a Crohn's disease activity index (CDAI) score <150 after 14 weeks of treatment. Blood samples were obtained at baseline and at weeks 4, 8, and 14. Adalimumab and infliximab levels were measured, receiver operating characteristic (ROC) curves were constructed, and the area under the ROC curve was calculated. RESULTS: One-hundred fifty patients with Crohn's disease were included, 79 (53%) received infliximab and 71 (47%) had CDAI > 150 at study entry. At week 14, 52 out of 71 patients with CDAI > 150 at baseline (73%) had clinical remission. There were no differences in infliximab levels between patients with and without remission (8 vs. 9.1 µg/mL, P > 0.05) or with and without response (7 vs. 11 µg/mL, P > 0.05) at week 14. There was a trend to higher levels of adalimumab concentration in responders in comparison with nonresponders (13 vs. 6.7 µg/mL, P = 0.05) and in patients who achieved remission in comparison with nonremitters (13.5 vs. 8.4 µg/mL, P = 0.06). In the multivariate analysis, no variable was predictive of short-term remission, including infliximab and adalimumab serum levels. CONCLUSION: Determining anti-TNF serum levels during the induction phase is not useful for predicting short-term remission in patients with Crohn's disease.