Influence of familial forms of inflammatory bowel disease on the use of immunosuppressants, biological agents, and surgery in the era of biological therapies. Results from the ENEIDA project.

BACKGROUND AND AIMS: Familial inflammatory bowel disease (IBD) history is a controversial prognostic factor in IBD. We aimed to evaluate the impact of a familial history of IBD on the use of medical and surgical treatments in the biological era. METHODS: Patients included in the prospectively maintained ENEIDA database and diagnosed with IBD after 2005 were included. Familial forms were defined as those cases with at least one first-degree relative diagnosed with IBD. Disease phenotype, the use of biological agents, or surgical treatments were the main outcomes. RESULTS: A total of 5263 patients [2627 Crohn's disease (CD); 2636 ulcerative colitis (UC)] were included, with a median follow-up of 31 months. Of these, 507 (10%) corresponded to familial forms. No clinical differences were observed between familial and sporadic IBD forms except a lower age at IBD diagnosis and a higher rate of males in familial forms of UC. In CD, the proportions of patients treated with thiopurines (54.4% vs 46.7%; P = .015) and survival time free of thiopurines (P = .009) were lower in familial forms. No differences were found regarding the use of biological agents. Concerning surgery, a higher rate of intestinal resections was observed in sporadic CD (14.8% vs 9.9%, P = .027). No differences were observed in UC. CONCLUSIONS: In the era of biological therapies, familial and sporadic forms of IBD show similar phenotypes and are managed medically in a similar way; whether these is due to lack of phenotypical differences or an effect of biological therapies is uncertain. What is already known on this topic: IBD's etiopathogenesis points to an interaction between environmental and genetic factors, being familial history a controversial prognostic factor. Biological agents use and need for surgery regarding familial or sporadic forms of IBDs present conflicting results. What this study adds: Familial and sporadic forms of IBD have similar phenotypes and are managed medically and surgically in a similar way. How this study might affect research, practice or policy: Familial aggregation should not be considered a factor associated with more aggressive disease.

Diffuse colonic capillary hemangioma mimicking ulcerative colitis.

Inflammatory bowel disease (IBD) diagnosis requires clinical, laboratory, endoscopic and histologic findings, and sometimes it can become a challenge. An exhaustive differential diagnosis with infectious disease, immunodeficiencies, hematologic, neoplastic, or vascular diseases must be made1, since prognosis and treatment vary depending on etiology. We present the case of a 62-year-old man, with no personal history of interest, who undergoes a colonoscopy after a positive colorectal cancer screening test (fecal occult blood test). In the endoscopy, a continuous involvement was observed from the anal margin to the splenic flexure, with erythematous mucosa, loss of vascular pattern, and alternating scar areas with neovessels. Histopathological findings were compatible with diffuse capillary hemangioma. Since no symptoms of gastrointestinal (GI) bleeding nor anemia were referred, periodic surveillance was carried out.

Varicella zoster virus encephalitis: a potentially serious complication during treatment with vedolizumab.

Vedolizumab is a monoclonal antibody that has demonstrated efficacy and a good safety profile in patients with inflammatory bowel disease. Varicella zoster virus encephalitis is a potentially serious complication not previously described with its use, highlighting the importance of vaccination, as well as early diagnosis and treatment of infections in this type of patients.

Recurrent abdominal pain as the only clinical manifestation of hereditary angioedema type II.

Recurrent abdominal pain is a common reason for consultation in Gastroenterology. The differential diagnosis includes hereditary angioedema (HAE), a rare disorder characterized by recurrent episodes of angioedema, without urticaria or pruritus, which most often affects the skin, but also mucosal tissues of the gastrointestinal tract, triggered by diverse factors such as infections, trauma, surgery, drugs, or stress. It is a disease with a difficult diagnosis due to its heterogeneous and transitory clinical features, so having a clinical suspicion in the appropriate context would allow the administration of a specific treatment and avoid unnecessary examinations. We present the case of a 19-year-old male followed-up for recurrent abdominal pain that, after numerous microbiological, endoscopic, and radiological examinations, complement tests were requested, obtaining low levels of C4 with increased levels of C1 inhibitor and reduced functional activity, being diagnosed with HAE type II.

Intestinal stenosis developed after a complete response to chemotherapy in a patient with Crohn´s disease and lymphoma of the jejunum.

An increased risk of hematologic malignancies secondary to long-term immunomodulators and biologics has been described in patients with inflammatory bowel disease1. Here, we present a case of jejunal stricture after chemotherapy treatment in a patient with ileal Crohn´s disease (CD) and jejunal lymphoma. The patient was a 32-year-old male with ileal CD in remission presenting with abdominal pain and distension. Abdominal computed tomography (CT) showed a poorly defined mass in the proximal jejunum, and positron emission tomography (PET) - CT showed hypermetabolic activity at that level. An upper endoscopy evidenced an indurated, friable circumferential mass causing a significant reduction of the intestinal lumen. Histological and cytometry findings led to a diagnosis of large B cell lymphoma, for which the patient received standard treatment (R-CHOP and IPI), achieving complete response. Eight months later, the patient reported abdominal pain and distention. Abdominal CT showed a thickening of a short segment of the proximal jejunum. An upper endoscopy showed a punctiform stenosis, while multiple biopsies showed neither histological recurrence of lymphoma nor signs of IBD. The patient was diagnosed with a post-chemotherapy stricture and underwent progressive endoscopic balloon dilatation. He finally was scheduled for laparoscopic small bowel resection. An histological analysis of the surgical piece revealed a granulomatous reaction with multinucleated foreign body-like giant cells, without evidence of malignancy (recurrence of lymphoma) nor inflammatory infiltrate suggesting CD. The patient currently remains asymptomatic with no new episodes of abdominal pain.

Ulcerative colitis induced by obinutuzumab in a patient treated for a folicular lymphoma.

An increasing use of immunomodulatory drugs has led to a corresponding increase in treatment-related pathologies such as inflammatory bowel disease. Here, we present a case of ulcerative colitis due to Obinutuzumab, an antiCD20 monoclonal approved for the treatment of Non-Hodgkin lymphomas.

Crohn's disease induced by ocrelizumab in a patient with multiple sclerosis.

Drug-induced inflammatory bowel disease (IBD) is a clinical entity on the rise due to the frequent use of immunomodulatory therapy. Here we report the case of Crohn's disease due to Ocrelizumab, a humanized anti-CD20 monoclonal antibody approved for the treatment of multiple sclerosis. The exact mechanism by which anti-CD20 antibodies can trigger IBD is unknown, but since IBD and multiple sclerosis are processes included within the spectrum of immunomediated diseases, we could suggest that Ocrelizumab could trigger IBD in genetically predisposed patients.

Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on screening and treatment of tuberculosis infection in patients with inflammatory bowel disease. / Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) sobre el cribado y tratamiento de la infección tuberculosa en pacientes con enfermedad inflamatoria intestinal.

There is evidence that following the recommendations on screening and treatment of tuberculosis infection does not completely prevent the onset of tuberculosis in patients with inflammatory bowel disease. This fact, and the increasing use of new biologics and immunomodulators, has led the Spanish Group Working on Crohn's Disease and Ulcerative Colitis to update their recommendations for the prevention of tuberculosis in patients with inflammatory bowel disease. Diagnostic methods for latent tuberculosis infection, different scenarios in which screening is to be performed, strategies to reduce the risk of tuberculosis once biological treatment is initiated and chemoprophylaxis guidelines for latent tuberculosis infection are reviewed, as well as the management of active tuberculosis during biological treatment. Finally, there is a summary of the current recommendations within the paper and in an algorithm.

Idiopathic acute pancreatitis in patients with inflammatory bowel disease: A multicenter cohort study.

BACKGROUND: Idiopathic acute pancreatitis (IAP) in patients with inflammatory bowel disease (IBD) is not well characterized. Our purpose was to better understand this condition and its natural history. METHODS: Retrospective cohort study conducted at nine Spanish IBD referral centers. Patients with IBD and a first episode of acute pancreatitis (AP) between 1998 and 2018 were included. Patients with a previous episode of AP or a diagnosis of chronic pancreatitis were excluded. IAP and non-IAP were compared by multivariate logistic regression and survival analysis. RESULTS: We identified 185 patients with IBD (68.7% Crohn's disease) and a first episode of AP. Thirty-eight of those 185 (20.6%) fulfilled criteria for IAP. There were no severe cases of IAP. On multivariate analysis, AP before IBD diagnosis (21.1% vs. 3.4%, p = 0.04) and ulcerative colitis (52.6% vs. 23.1%, p = 0.002) were significantly more common in IAP. Further work-up was performed in 16/38 (42%) IAP patients, and a cause was identified in 6/16 (37.5%). Median time from AP to the end of follow-up was 6.3 years (3.1-10). Five-year risk of AP recurrence was significantly higher in IAP group (28% vs. 5.1%, log-rank p = 0.001), with a median time to first recurrence of 4.4 months (2.9-12.2). CONCLUSIONS: IAP represents the second cause of AP in patients with IBD. It is more frequent in ulcerative colitis, and presents a high risk of recurrence. Additional imaging work-up after a first episode of IAP in IBD patients is highly advisable, as it identifies a cause in more than one-third of cases.

The Harvey-Bradshaw Index Adapted to a Mobile Application Compared with In-Clinic Assessment: The MediCrohn Study.

Objectives: Mobile apps are useful tools in e-health and self-management strategies in disease monitoring. We evaluated the Harvey-Bradshaw index (HBI) mobile app self-administered by the patient to see if its results agreed with HBI in-clinic assessed by a physician. Methods: Patients were enrolled in a 4-month prospective study with clinical assessments at months 1 and 4. Patients completed mobile app HBI and within 48 h, HBI was performed by a physician (gold standard). HBI scores characterized Crohn's disease (CD) as remission <5 or active ≥5. We determined agreement per item and total HBI score and intraclass correlation coefficients (ICCs). Bland-Altman plot was performed. HBI changes in disease activity from month 1 to month 4 were determined. Results: A total of 219 patients were enrolled. All scheduled assessments (385 pairs of the HBI questionnaire) showed a high percentage of agreement for remission/activity (92.4%, κ = 0.796), positive predictive value (PPV) for remission of 98.2%, and negative predictive value of 76.7%. High agreement was also found at month 1 (93.15%, κ = 0.82) and month 4 (91.5%, κ = 0.75). Bland-Altman plot was more uniform when the HBI mean values were <5 (remission). ICC values were 0.82, 0.897, and 0.879 in all scheduled assessments, 1 and 4 months, respectively. Conclusions: We found a high percentage of agreement between patients' self-administered mobile app HBI and in-clinic physician assessment to detect CD activity with a remarkably high PPV for remission. The mobile app HBI might allow a strict control of inflammation by remote monitoring and flexible follow-up of CD patients. Reduction of sanitary costs could be possible.

Efficacy and safety of the SB Knife™ Jr. for the treatment of Zenker's diverticulum: a case series.

BACKGROUND AND AIMS: the stag-beetle knife is a new scissor-like endoscopic device that can be used for the treatment of Zenker's diverticulum, although experience is limited. The aim of this study was to evaluate the efficacy and safety of the SB Knife™ for the endoscopic treatment of Zenker's diverticulum. METHODS: a single-center prospective study of 16 patients was performed between May 2017 and April 2019. The rate of complications and symptom changes was evaluated. RESULTS: the median age was 78 years and 62.5% of the patients were male. All had dysphagia, 43.8% choking, 31.3% regurgitation and 6.3% respiratory symptoms. The median size of the diverticulum was 20 mm and the median follow-up was 281 days. There were no intra-procedure complications and only one major post-procedure complication was reported that was a microperforation. All patients had clinical improvement. Two patients had relapsing symptoms and were successfully treated with the same method. CONCLUSIONS: the SB Knife™ seems to be a safe and effective technique for the treatment of Zenker's diverticulum.

Association between disease activity and quality of life in ulcerative colitis: Results from the CRONICA-UC study.

BACKGROUND AND AIM: In ulcerative colitis (UC), the main goals of treatment are to control disease activity and normalize health-related quality of life (HRQoL). In this study, we explored the relationship between disease activity (measured using the Simple Clinical Colitis Activity Index [SCCAI]) and patient HRQoL (measured using the EuroQoL [EQ]-5D-5L). METHODS: A total of 199 patients with UC were followed for 6 months. At months 3 and 6, patients completed an online SCCAI. Within 2 days of completing the SCCAI, patients completed an at-clinic EQ-5D-5L questionnaire and the treating gastroenterologist completed the SCCAI. RESULTS: A consistent and approximately linear relationship was identified between patient HRQoL and patient-completed and physician-completed SCCAIs. A lower SCCAI score corresponded to a higher EQ-5D-5L index value. Correlation between EQ-5D-5L index values and patient-completed online SCCAIs was moderate (ρ -0.49; P < 0.001) and similar to that between EQ-5D-5L index values and physician-completed SCCAIs (ρ -0.53; P < 0.001). A decrease in the EQ-5D-5L index was already observed at an SCCAI score of 2, commonly regarded as remission. A 1-point increase in the patient SCCAI corresponded to an average change of -0.027 (standard deviation, -0.032 to -0.022) in the EQ-5D-5L index, whereas a 1-point increase in the physician SCCAI corresponded to an average change of -0.030 (standard deviation, -0.036 to -0.025). CONCLUSIONS: Health-related quality of life measured using the EQ-5D-5L questionnaire is proportionally related to disease activity in patients with UC. In line with the treat-to-target objective in UC, complete control of all symptoms is required to achieve optimal improvement in patient HRQoL.

Association between psychological measures with inflammatory anddisease-related markers of inflammatory bowel disease.

OBJECTIVE: This study aimed at investigating the associations between inflammatory mediators, symptoms and psychological disturbances in inflammatory bowel disease (IBD) patients. METHODS: IBD patients and patient controls were examined during a single visit to a gastroenterology clinic. Disease activity was assessed using the Mayo index for ulcerative colitis (UC), inflammatory bowel disease questionnaire (IBDQ), Crohn's disease activity index (CDAI) and Crohn's disease endoscopic index of severity (CDEIS). Gene expression of inflammatory mediators were measured in intestinal biopsies and whole blood samples along with circulating concentrations of interleukin (IL)-6, interferon (IFN)γ, C-reactive protein (CRP), kynurenine and tryptophan. Validated depression, anxiety and quality of life scores were used to assess psychological well-being. RESULTS: Patients who were symptomatic had the highest depression and anxiety scores, together with increased intestinal expression of IL-1ß, IL-6 and matrix metalloproteinase-9, increased circulating IL-6 and CRP, and an increased circulating kynurenine:tryptophan ratio. Increased Hamilton depression (HAM-D) scores in IBD patients were observed independent of the psychological impact of acute symptoms. CONCLUSIONS: Active IBD is associated with symptoms of depression and anxiety and with a raised circulating inflammatory mediator profile. Patients with active IBD exhibiting psychological symptoms should undergo psychological evaluation to ensure the psychological aspects of the condition are considered and addressed.

Diagnostic Performance of the Simple Clinical Colitis Activity Index Self-Administered Online at Home by Patients With Ulcerative Colitis: CRONICA-UC Study.

OBJECTIVES: New e-health technologies can improve patient-physician communication and contribute to optimal patient care. We compared the diagnostic performance of the Simple Clinical Colitis Activity Index (SCCAI) self-administered by patients with ulcerative colitis (UC) at home (through a website) with the in-clinic gastroenterologist-assessed SCCAI. METHODS: Patients were followed-up over 6 months. At months 3 and 6, patients completed the SCCAI online at home; within 48 h, gastroenterologists (blinded to patients' scores) completed the in-clinic SCCAI (reference). SCCAI scores were dichotomized to remission or active disease, and SCCAI changes in disease activity from month 3 to 6 were classed as worsening, stability, or improvement. RESULTS: A total of 199 patients (median age: 38 years; 56% female) contributed with 340 pairs of questionnaires. Correlation of SCCAI scores by patients and physicians was good (Spearman's ρ=0.79), with 85% agreement for remission or activity (95% CI: 80.8-88.6, κ=0.66). The negative predictive value for active disease was 94.5% (91.4-96.6); the positive predictive value was 68.0% (58.8-69.2). Agreement between patient and physician was higher in the 168 month 6 pairs than in the 172 month 3 pairs of questionnaires (89.3% (83.6-93.1) vs. 80.8% (74.2-86.0), P=0.027). CONCLUSIONS: In patients with UC, SCCAI self-administration via an online tool resulted in a high percentage of agreement with evaluation by gastroenterologists, with a remarkably high negative predictive value for disease activity. Remote monitoring of UC patients is possible and might reduce hospital visits.

Risk factors for tuberculosis in inflammatory bowel disease: anti-tumor necrosis factor and hospitalization.

AIMS: To determine risk factors for active tuberculosis in patients with inflammatory bowel diseases. METHODS: Retrospective, case-control study at 4 referral hospitals in Spain. Cases developed tuberculosis after a diagnosis of inflammatory bowel disease. Controls were inflammatory bowel disease patients who did not develop tuberculosis. For each case, we randomly selected 3 controls matched for sex, age (within 5 years) and time of inflammatory bowel disease diagnosis (within 3 years). Inflammatory bowel disease characteristics, candidate risk factors for tuberculosis and information about the tuberculosis episode were recorded. Multivariate analysis and a Chi-squared automatic interaction detector were used. RESULTS: Thirty-four cases and 102 controls were included. Nine of the 34 cases developed active tuberculosis between 1989 and 1999, and 25 became ill between 2000 and 2012. Multivariate regression showed an association between active tuberculosis and anti-TNF (tumor necrosis factor) therapy in the previous 12 months (OR 7.45; 95% CI, 2.39-23.12; p = .001); hospitalization in the previous 6 months (OR 4.38; 95% CI, 1.18-16.20; p = .027); and albumin levels (OR 0.88; 95% CI, 0.81-0.95; p = .001). The median time between the start of biologic therapy and the onset of active tuberculosis was 13 (interquartile range, 1-58) months. Tuberculosis developed after a year of anti-TNF therapy in 53%, and late reactivation occurred in at least 3 of 8 patients. CONCLUSIONS: The main risks factors for developing tuberculosis were anti-TNF therapy and hospitalization. Over half the cases related to anti-TNF treatment occurred after a year.

Treatment preferences of patients with Crohn's disease: Development of the IMPLICA questionnaire.

INTRODUCTION AND OBJECTIVE: Patient preferences with respect to available therapies must be taken into account if the quality of care of patients with Crohn´s disease is to be improved. The objective was to develop the IMPLICA preferences questionnaire for Crohn´s disease patients treated with biological therapies. METHODS: As per standard methodology, the questionnaire was developed in Spanish language, in five stages: 1. Literature review to identify attributes related to biological therapies in Crohn´s disease; 2. Expert meeting to identify attributes most relevant for patients; 3. Scoring of the most relevant attributes and generation of scenarios; 4. Patient comprehension test for selection and validation of scenarios; and 5. Final list of scenarios and qualitative evaluation of those most accepted by patients. RESULTS: Three attributes related to various characteristics of biological treatments were selected: route of administration, place/duration of administration and person administering the treatment; a combination of them produced seven possible scenarios. The comprehension test gave rise to significant modifications in the instructions, text of the scenarios and response categories. CONCLUSION: IMPLICA is the first questionnaire to evaluate treatment preferences of Crohn´s disease patients receiving biological therapies. This questionnaire facilitates patient´s selection of the most appropriate real world treatment option and, therefore, it can be considered a useful tool when deciding the most appropriate and feasible treatment in normal clinical practice.

Effectiveness and safety of a third-line rescue treatment for acute severe ulcerative colitis refractory to infliximab or ciclosporin (REASUC study).

BACKGROUND: The advent of new therapeutic agents and the improvement of supporting care might change the management of acute severe ulcerative colitis (ASUC) and avoid colectomy. AIMS: To evaluate the colectomy-free survival and safety of a third-line treatment in patients with ASUC refractory to intravenous steroids and who failed either infliximab or ciclosporin. METHODS: Multicentre retrospective cohort study of patients with ASUC refractory to intravenous steroids who had failed infliximab or ciclosporin and received a third-line treatment during the same hospitalisation. Patients who stopped second-line treatment due to disease activity or adverse events (AEs) were eligible. We assessed short-term colectomy-free survival by logistic regression analysis. Kaplan-Meier curves and Cox regression models were used for long-term assessment. RESULTS: Among 78 patients, 32 received infliximab and 46 ciclosporin as second-line rescue treatment. Third-line treatment was infliximab in 45 (58%), ciclosporin in 17 (22%), tofacitinib in 13 (17%) and ustekinumab in 3 (3.8%). Colectomy was performed in 29 patients (37%) during follow-up (median 21 weeks). Of the 78 patients, 32 and 18 were in clinical remission at, respectively, 12 and 52 weeks. At the last visit, 25 patients were still on third-line rescue treatment, while 12 had stopped it due to clinical remission. AEs were reported in 26 (33%) patients. Two patients died (2.6%), including one following colectomy. CONCLUSION: Third-line rescue treatment avoided colectomy in over half of the patients with ASUC and may be considered a therapeutic strategy.

Comparative Study of the Effectiveness of Vedolizumab Versus Ustekinumab After Anti-TNF Failure in Crohn's Disease (Versus-CD): Data from the ENEIDA Registry.

BACKGROUND: Both vedolizumab and ustekinumab are approved for the management of Crohn's disease [CD]. Data on which one would be the most beneficial option when anti-tumour necrosis factor [anti-TNF] agents fail are limited. AIMS: To compare the durability, effectiveness, and safety of vedolizumab and ustekinumab after anti-TNF failure or intolerance in CD. METHODS: CD patients from the ENEIDA registry who received vedolizumab or ustekinumab after anti-TNF failure or intolerance were included. Durability and effectiveness were evaluated in both the short and the long term. Effectiveness was defined according to the Harvey-Bradshaw index [HBI]. The safety profile was compared between the two treatments. The propensity score was calculated by the inverse probability weighting method to balance confounder factors. RESULTS: A total of 835 patients from 30 centres were included, 207 treated with vedolizumab and 628 with ustekinumab. Dose intensification was performed in 295 patients. Vedolizumab [vs ustekinumab] was associated with a higher risk of treatment discontinuation (hazard ratio [HR] 2.55, 95% confidence interval [CI]: 2.02-3.21), adjusted by corticosteroids at baseline [HR 1.27; 95% CI: 1.00-1.62], moderate-severe activity in HBI [HR 1.79; 95% CI: 1.20-2.48], and high levels of C-reactive protein at baseline [HR 1.06; 95% CI: 1.02-1.10]. The inverse probability weighting method confirmed these results. Clinical response, remission, and corticosteroid-free clinical remission were higher with ustekinumab than with vedolizumab. Both drugs had a low risk of adverse events with no differences between them. CONCLUSION: In CD patients who have failed anti-TNF agents, ustekinumab seems to be superior to vedolizumab in terms of durability and effectiveness in clinical practice. The safety profile is good and similar for both treatments.

Serum and Urine Metabolomic Profiling of Newly Diagnosed Treatment-Naïve Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a prevalent chronic noncurable disease associated with profound metabolic changes. The discovery of novel molecular indicators for unraveling IBD etiopathogenesis and the diagnosis and prognosis of IBD is therefore pivotal. We sought to determine the distinctive metabolic signatures from the different IBD subgroups before treatment initiation. METHODS: Serum and urine samples from newly diagnosed treatment-naïve IBD patients and age and sex-matched healthy control (HC) individuals were investigated using proton nuclear magnetic resonance spectroscopy. Metabolic differences were identified based on univariate and multivariate statistical analyses. RESULTS: A total of 137 Crohn's disease patients, 202 ulcerative colitis patients, and 338 HC individuals were included. In the IBD cohort, several distinguishable metabolites were detected within each subgroup comparison. Most of the differences revealed alterations in energy and amino acid metabolism in IBD patients, with an increased demand of the body for energy mainly through the ketone bodies. As compared with HC individuals, differences in metabolites were more marked and numerous in Crohn's disease than in ulcerative colitis patients, and in serum than in urine. In addition, clustering analysis revealed 3 distinct patient profiles with notable differences among them based on the analysis of their clinical, anthropometric, and metabolomic variables. However, relevant phenotypical differences were not found among these 3 clusters. CONCLUSIONS: This study highlights the molecular alterations present within the different subgroups of newly diagnosed treatment-naïve IBD patients. The metabolomic profile of these patients may provide further understanding of pathogenic mechanisms of IBD subgroups. Serum metabotype seemed to be especially sensitive to the onset of IBD.