Location, morphology and invasiveness of lateral spreading tumors in the colorectum differ between two large cohorts from an eastern and western country.

BACKGROUND AND STUDY AIMS: Data from Japanese series show that surface morphology of laterally spreading tumors (LST) in the colon identifies lesions with different incidence and pattern of submucosal invasion. Such data from western countries are scarce. We compared clinical and histological features of LST in a western country and an eastern country, with special interest on mucosal invasiveness of LST, and investigated the effect of clinical factors on invasiveness in both countries. PATIENTS AND METHODS: Patients with LST lesions ≥20mm were included from a multicenter prospective registry in Spain and from a retrospective registry from the National Cancer Center Hospital East, Japan. The primary outcome was the presence of submucosal invasion in LST. The secondary outcome was the presence of high-risk histology, defined as high-grade dysplasia or submucosal invasion. RESULTS: We evaluated 1102 patients in Spain and 663 in Japan. Morphological and histological characteristics differed. The prevalence of submucosal invasion in Japan was six-fold the prevalence in Spain (Prevalence Ratio PR=5.66; 95%CI: 3.96, 8.08), and the prevalence of high-risk histology was 1.5 higher (PR=1.44; 95%CI: 1.31, 1.58). Compared to the granular homogeneous type and adjusted by clinical features, granular mixed, flat elevated, and pseudo-depressed types were associated with higher odds of submucosal invasion in Japan, whereas only the pseudo-depressed type showed higher risk in Spain. Regarding high-risk histology, both granular mixed and pseudo-depressed were associated with higher odds in Japan, compared with only the granular mixed type in Spain. CONCLUSION: This study reveals differences in location, morphology and invasiveness of LST in an eastern and a western cohort.

Extraintestinal Manifestations in Patients with Inflammatory Bowel Disease: Study Based on the ENEIDA Registry.

BACKGROUND: Patients with inflammatory bowel disease (IBD) may present extraintestinal manifestations (EIMs) that affect the joints, skin, eyes, and hepatobiliary area, among others. AIMS: Our aim was to analyse the prevalence and characteristics of EIMs in patients with IBD and to identify the possible risk factors associated with the development of EIMs in the largest series published to date. METHODS: Observational, cross-sectional study including patients from the Spanish ENEIDA registry promoted by GETECCU. We retrospectively identified all cases of EIMs in the ENEIDA registry until January 2018. RESULTS: The study included 31,077 patients, 5779 of whom had at least one EIM (global prevalence 19%; 95% CI 18.2-19.0). Among the different types of EIMs, rheumatic manifestations had a prevalence of 13% (95% CI 12.9-13.7; 63% of EIMs), with a prevalence of 5% (95% CI 4.7-5.2) for mucocutaneous manifestations, 2.1% (95% CI 1.9-2.2) for ocular manifestations, and 0.7% (95% CI 0.6-0.8) for hepatobiliary manifestations. The multivariable analysis showed that the type of IBD (Crohn's disease, p < 0.001), gender (female, p < 0.001), the need for an immunomodulator (p < 0.001) or biologic drugs (p < 0.001), a previous family history of IBD (p < 0.001), and an extensive location of IBD (p < 0.001) were risk factors for the presence of EIMs. CONCLUSIONS: One-fifth of patients with IBD may have associated EIMs, with rheumatic manifestations as the most frequent (> 60% of EIMs). Female patients with severe Crohn's disease represent the group with the highest risk of developing EIMs. These patients should therefore be specially monitored and referred to the corresponding specialist when suggestive symptoms appear.

Long-Term Follow-Up of Patients Treated with Infliximab for Ulcerative Colitis: Predictive Factors of Response-An Observational Study.

AIM: To evaluate the early and long-term efficacy of infliximab in ulcerative colitis and to determine predictors of response and colectomy. METHODS: This is an ambidirectional cohort study in a tertiary referral center including patients who started infliximab within 2005 and 2008 and monitored until 2014. Efficacy was evaluated by partial Mayo scores at weeks 2, 4, 8, 30, and 54. Long-term treatment maintenance with infliximab and colectomy requirements were recorded. RESULTS: Fifty-three patients were included with a median follow-up of 69.5 months. Clinical remission at the time point assessments was 40.8, 47.2, 54.7, 54.7, and 49.1 %. At the time of maximal follow-up, the proportion of patients under infliximab maintenance was 24.5 %. A higher level of albumin (OR 1.4, CI 95 % 1.06-1.8; p = 0.017) was predictive of a higher remission rate at week 8. Concomitant immunomodulators beyond 6 months were predictive of infliximab's long-term maintenance (OR 15.8, CI 95 % 1.8-135.4; p = 0.012). Colectomy was required in 41.5 %. Factors associated with a higher rate of colectomy at week 54 were previous treatment with cyclosporine (OR 3.4, CI 95 % 1.2-9.7; p = 0.012), absence of response at week 8 (OR 10.3, CI 95 % 3.3-31.7; p < 0.001), and not receiving concomitant immunomodulators (OR 4.1, CI 95 % 1.8-9; p = 0.002). Colectomy rates within the first 54 weeks were closely dependent on the number of variables present: none (0 %), 1 (26.3 %), 2 (71.4 %), or 3 (100 %) of them (log rank <0.0001). CONCLUSIONS: Low albumin, previous treatment with cyclosporine, absence of a concomitant immunomodulator, and lack of response at week 8 negatively affected the efficacy of infliximab in ulcerative colitis.

Diagnostic accuracy of magnetic resonance colonography for the evaluation of disease activity and severity in ulcerative colitis: a prospective study.

OBJECTIVE: The aim of this study was to determine the diagnostic accuracy of magnetic resonance colonography (MRC) for the evaluation of disease activity and severity in patients with ulcerative colitis (UC) using endoscopy as the reference standard. METHODS: Fifty patients with UC underwent colonoscopy and MRC for the evaluation of disease activity. All patients were prospectively and consecutively included. Endoscopic activity was evaluated globally and on a segment basis using the modified Baron score (MBS), and also classified as absent, mild to moderate (inflammation without ulcers) or severe (presence of ulceration). MRC parameters evaluated in each segment were: wall thickness, pre- and post-contrast wall signal intensity, relative contrast enhancement (RCE), mural oedema, ulcers, enlarged lymph nodes and the comb sign. RESULTS: Independent predictors for endoscopic activity on a segment basis were RCE (p=0.006), presence of oedema (p=0.003), enlarged lymph nodes (p<0.001) and the comb sign (p<0.001). A segmental simplified MRC index (MRC-S) ≥ 1 detected endoscopic inflammation with high diagnostic accuracy (sensitivity 87%, specificity 88%, area under the curve (AUC) 0.95; p<0.001). MRC-S index ≥ 2 detected severe lesions with high sensitivity (83%) and specificity (82%) with an AUC of 0.91 (p<0.001). The MRC-S index strongly correlated with the MBS (r=0.81, p<0.001) and with the subjective assessment of the radiologists for the evaluation of disease severity (r=0.77, p<0.001). CONCLUSIONS: MRC has a high accuracy for the diagnosis of disease activity and severity in UC.

Role of 3.0-T MR colonography in the evaluation of inflammatory bowel disease.

Conventional colonoscopy combined with histologic analysis represents the standard of reference for the evaluation of colorectal disease and is usually the initial examination in patients with a suspected or established diagnosis of inflammatory bowel disease (IBD). However, it is increasingly being recognized that colonoscopy is limited to providing information regarding mucosal alterations. Colonoscopy cannot help estimate the depth of involvement of colonic lesions and does not provide information regarding the presence of extraluminal complications such as abscesses or fistulas. Recent technologic advances in magnetic resonance (MR) imaging, with its high spatial and tissue resolution, have raised expectations as to the potential role of this modality in the evaluation of colonic lesions in patients with IBD, as either a complement or an alternative to colonoscopy. MR colonography allows the characterization of colonic changes in acute and chronic IBD and can depict a wide spectrum of related lesions, including ulcers, edema, wall thickening, hyperemia, and fistulas, as well as potential extraluminal complications. The bulk of available evidence indicates that MR colonography can be useful as a problem-solving tool in the evaluation of IBD, as an alternative to colonoscopy whenever tissue sampling is not required, and for the assessment of the entire colon in cases of incomplete colonoscopy.

Are we giving biologics too late? The case for early versus late use.

Corticosteroids and immunomodulators have been the mainstay therapies for Crohn's disease. Corticosteroids are highly effective to control symptoms in the short-term, but they are not effective in maintaining remission, they heal the mucosa in a reduced proportion of cases, and long-time exposure is associated with an increased risk of infections and mortality. Immunomodulators, azathioprine and methotrexate, heal the mucosa in a higher proportion of patients that corticosteroids but their onset of action is slow and they benefit less than half of patients with Crohn's disease. In the last decade, medical therapy for Crohn's disease has experienced a remarkable change due to the introduction of biologic therapy, and particularly the use of anti-tumour necrosis factor-alpha agents. Infliximab, adalimumab, and certolizumab pegol have demonstrated efficacy for induction and maintenance of remission in active Crohn's disease. These agents have raised the bar for what is a suitable symptomatic response in Crohn's disease and modification of the natural history of the disease has become a major goal in the treatment of Crohn's disease. There are several data in the literature that suggest that early use of biologic therapy and achievement of mucosal healing contribute to disease course modification. However, many questions on early biological therapy for Crohn's disease remain still unanswered.

Rate of adverse events of gastroduodenal snare polypectomy for non-flat polyp is low: A prospective and multicenter study.

AIM: To evaluate the rate of adverse events (AEs) during consecutive gastric and duodenal polypectomies in several Spanish centers. METHODS: Polypectomies of protruded gastric or duodenal polyps ≥ 5 mm using hot snare were prospectively included. Prophylactic measures of hemorrhage were allowed in predefined cases. AEs were defined and graded according to the lexicon recommended by the American Society for Gastrointestinal Endoscopy. Patients were followed for 48 h, one week and 1 mo after the procedure. RESULTS: 308 patients were included and a single polypectomy was performed in 205. Only 36 (11.7%) were on prior anticoagulant therapy. Mean polyp size was 15 ± 8.9 mm (5-60) and in 294 cases (95.4%) were located in the stomach. Hemorrhage prophylaxis was performed in 219 (71.1%) patients. Nine patients presented AEs (2.9%), and 6 of them were bleeding (n = 6, 1.9%) (in 5 out of 6 AE, different types of endoscopic treatment were performed). Other 24 hemorrhagic episodes could be managed without any change in the outcome of the endoscopy and, consequently, were considered incidents. We did not find any independent risk factor of bleeding. CONCLUSION: Gastroduodenal polypectomy using prophylactic measures has a rate of AEs small enough to consider this procedure a safe and effective method for polyp resection independently of the polyp size and location.

Interleukin-19 impairment in active Crohn's disease patients.

The exact function of interleukin-19 (IL-19) on immune response is poorly understood. In mice, IL-19 up-regulates TNFα and IL-6 expression and its deficiency increases susceptibility to DSS-induced colitis. In humans, IL-19 favors a Th2 response and is elevated in several diseases. We here investigate the expression and effects of IL-19 on cells from active Crohn's disease (CD) patient. Twenty-three active CD patients and 20 healthy controls (HC) were included. mRNA and protein IL-19 levels were analyzed in monocytes. IL-19 effects were determined in vitro on the T cell phenotype and in the production of cytokines by immune cells. We observed that unstimulated and TLR-activated monocytes expressed significantly lower IL-19 mRNA in active CD patients than in HC (logFC = -1.97 unstimulated; -1.88 with Pam3CSK4; and -1.91 with FSL-1; p<0.001). These results were confirmed at protein level. Exogenous IL-19 had an anti-inflammatory effect on HC but not on CD patients. IL-19 decreased TNFα production in PBMC (850.7 ± 75.29 pg/ml vs 2626.0 ± 350 pg/ml; p<0.01) and increased CTLA4 expression (22.04 ± 1.55% vs 13.98 ± 2.05%; p<0.05) and IL-4 production (32.5 ± 8.9 pg/ml vs 13.5 ± 2.9 pg/ml; p<0.05) in T cells from HC. IL-10 regulated IL-19 production in both active CD patients and HC. We observed that three of the miRNAs that can modulate IL-19 mRNA expression, were up-regulated in monocytes from active CD patients. These results suggested that IL-19 had an anti-inflammatory role in this study. Defects in IL-19 expression and the lack of response to this cytokine could contribute to inflammatory mechanisms in active CD patients.

Observational study on the efficacy of adalimumab for the treatment of ulcerative colitis and predictors of outcome.

BACKGROUND: Information on efficacy and predictors of response to adalimumab in ulcerative colitis (UC) clinical practice is limited. AIM: Assessment of response to adalimumab and its predictors in an observational cohort study. METHODS: Retrospective cohort study based on data obtained from ENEIDA registry. All patients diagnosed with UC treated with adalimumab were included. Response to adalimumab was evaluated at weeks 12, 28, and 54 according to the partial Mayo score, and requirement of colectomy until end of follow-up. RESULTS: 48 patients with UC treated with adalimumab were included; 39 (81.3%) had previously received infliximab. Response rates at weeks 12, 28 and 54 were 70.8%, 43.2% and 35% respectively. Response to prior treatment with infliximab was the only predictive factor of response to adalimumab at week 12, which was obtained in 90% of infliximab remitters, 53.8% of responders and 33.3% of primary non-responders (p=0.01). Colectomy was required in 11 patients (22.9%), after a mean time of 205 days. The only clinical independent predictor of colectomy was non-response to adalimumab at week 12: colectomy rates were 5/34 (14.7%) in responders and 6/14 (42.9%) in non-responders (p=0.035), time free of colectomy was significantly reduced in non-responders (p=0.01). Adalimumab withdrawal due to adverse events occurred in 4.2% of patients. CONCLUSION: This study shows that adalimumab is an effective treatment in patients with UC. If used as a second anti-TNF, previous achievement of remission with the first anti-TNF predicts response, and failure to achieve response at week 12 predicts colectomy.

Efficacy of adalimumab rescue therapy in patients with chronic refractory pouchitis previously treated with infliximab: a case series.

AIM: In refractory pouchitis, infliximab (IFX) has been used as rescue therapy; however, there is no clinical evidence for the use of adalimumab (ADA). The aim of this study was to report the efficacy of ADA in patients with refractory pouchitis previously treated with IFX. METHODS: A retrospective, open-label, case series was designed. Patients with chronic refractory pouchitis treated with ADA were included. All patients were previously treated with IFX. The short-term and mid-term efficacy of ADA was evaluated. RESULTS: Eight patients with chronic refractory pouchitis treated with ADA were included. After 8 weeks, 13% of the patients achieved remission and 62% showed a clinical response. At week 26, 13% achieved remission and 38% showed a clinical response. At week 52, 50% of the patients avoided a permanent ileostomy but only 25 achieved remission. CONCLUSION: ADA treatment was found to be an alternative for patients with chronic refractory pouchitis previously treated with IFX.

WITHDRAWN: Cell therapies for inflammatory bowel disease.

Ahead of Print article withdrawn by publisher. Present therapy of inflammatory bowel diseases (IBD) is aimed at relieving inflammation and treating signs and symptoms. Despite an optimized use of immunosuppressors and the new biologic agents, the need for intestinal resection in Crohn's disease (CD)has remained stable.1[1] Primary and secondary failure to respond to approved therapies, and in some cases inability to provide a surgical solution to a particular patient due to extension and/or location of lesions, represent unmet needs in the treatment of IBD. Two streams of research, experimental and clinical, are the origin of the increasing utilization of cell therapies for severe immune-mediated diseases including IBD, these include stem cell therapies, and selected/conditioned immune cell therapy, such as dendritic and regulatory T cells (Tregs). Over the last decade, significant responses have been documented to hematopoietic stem cells transplantation (HSCT) in many therapy-resistant immune-mediated disorders. Durable remission after immune reconstitution and tissue remodeling suggests an effect beyond profound immunosuppression. Although promising, HSCT for CD is still experimental and its toxicity leaves this option for a considerably reduced number of refractory patients in whom the disease is not amenable to surgical resection. In CD, where loss of tolerance towards commensal bacteria has been invoked in disease development, it would be justified to test the efficacy of tolerance-promoting cell therapies. Various approaches are being explored and have shown promising results in experimental models of autoimmunity. These include administration of mesenchimal stem cells, Tregs or tolerogenic dendritic cells.

Magnetic resonance imaging for evaluation of Crohn's disease: validation of parameters of severity and quantitative index of activity.

BACKGROUND: The use of magnetic resonance imaging (MRI) for assessment of Crohn's disease (CD) is expanding. The aim of this study is to define and provide an external validation of the MRI predictors of active CD, severe CD, and a quantitative Magnetic Resonance Index of Activity (MaRIA). METHODS: In all, 48 patients with clinically active (n = 29) or inactive (n = 19) CD underwent ileocolonoscopy (reference standard) and MRI. T2-weighted and pre- and postcontrast-enhanced T1-weighted sequences were acquired. Endoscopic activity was evaluated by the Crohn's Disease Endoscopic Index of Severity (CDEIS), and also classified as absent, mild (inflammation without ulcers), or severe (presence of ulceration). RESULTS: In complete agreement with a previous derivation study, independent predictors of disease severity using CDEIS as a reference were wall thickness, relative contrast enhancement (RCE), presence of edema, and ulcers on MRI. Estimation of activity in each segment using this regression model, or another with simplified coefficients (MaRIA(S) = 1.5*wall thickness + 0.02*RCE + 5*edema + 10*ulceration) correlated with CDEIS (r = 0.798, P< 0.001; r = 0.80 P < 0.001, respectively). In the validation cohort both indexes had a high and equal accuracy for diagnosis of active disease: receiver operator characteristic (ROC) area 0.93, sensitivity 0.87, specificity 0.87 using a cutoff point ≥ 7, and for diagnosis of severe disease: ROC area 0.96, sensitivity 0.92, specificity 0.92 using a cutoff point ≥ 11. The total of segment values (MaRIA(T)) correlated with global CDEIS (r = 0.83, P< 0.001). CONCLUSIONS: The MRI variables that should be evaluated in clinical practice to diagnose active CD and severe CD are validated, as well as the quantitative index of activity for use in research studies.

Methotrexate in ulcerative colitis: a Spanish multicentric study on clinical use and efficacy.

BACKGROUND: Few data are available on the efficacy of methotrexate (MTX) in ulcerative colitis (UC). AIM: To evaluate the efficacy and safety of MTX in UC patients. PATIENTS AND METHODS: UC patients who had been treated with MTX were identified from the databases of 8 Spanish IBD referral hospitals. Patients were included in the study if they received MTX for steroid dependency or steroid refractoriness. Therapeutic success was defined as the absence of UC-related symptoms, complete steroid withdrawal and no requirement of rescue therapies within the first 6 months after starting MTX. RESULTS: Forty patients were included, 70% treated for steroid dependency and 27% for steroid refractoriness. Thiopurines had been previously attempted in 87.5% of patients. The median dose of MTX used for induction was 25mg (IIQ 17.5-25) weekly given parenterally in 82.5% of cases. Eighty-five percent of patients were on steroids when MTX was started. Forty-five percent of patients met criteria for therapeutic success. Initial treatment failures were mainly due to inefficacy (50%) or intolerance (36%). After a median follow-up of 28 months (IQR 22-47), 38% of patients with initial therapeutic success required new steroid courses, 22% started biological therapy, and only 1 patient required colectomy. The cumulative probability of maintaining steroid-free clinical remission was 60%, 48%, and 35% at 6, 12, and 24 months after starting MTX, respectively. Eleven patients (27.5%) experienced adverse events, leading to MTX discontinuation in only 8 of them. CONCLUSIONS: MTX appears to be effective to maintain clinical remission in UC, at least in the short-term, with an acceptable safety profile.

MDP-Induced selective tolerance to TLR4 ligands: impairment in NOD2 mutant Crohn's disease patients.

BACKGROUND: Pathogen infection is a complex process in which several pathogen-recognition receptor (PRR) pathways are activated to induce proinflammatory mediators. The activation of multiple PRRs suggests an interaction between Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptor (NOD) signaling pathways. METHODS: To understand the modulation induced by NOD2 signals on successive responses to pathogen-associated molecular patterns (PAMPs), we examined how muramyl dipeptide (MDP) pretreatment reprograms the MDP+LPS (lipopolysaccharide) response of monocytes from human peripheral blood. RESULTS: Preexposure to bacterial MDP components induced selective tolerance to a subsequent NOD2+TLR4 stimulation. MDP pretreatment inhibited the production of tumor necrosis factor alpha (TNFalpha) and interleuken 10 (IL10), whereas IL6 and IL8 remained unaffected. MDP-induced tolerance was independent of receptor downregulation but was associated with reduced levels of phosphorylated TAK1 and abrogated phosphorylation of the downstream MAPK.Since Nod2 mutations have been associated with susceptibility to develop Crohn's disease (CD), we compared the MDP-induced tolerance in healthy donors and CD patients with compound heterozygous Nod2 mutations (Mut-Nod2) expressing variant NOD2 proteins. MDP-induced tolerance in Mut-Nod2 patients reduced IL10 but not TNFalpha production. In contrast with healthy donors, a p38-independent TNFalpha production was observed during the kinetics of the MDP+LPS response in Mut-Nod2 patients. CONCLUSIONS: Our findings suggest that the selective tolerance induced by MDP in healthy donors was related to the modulation of a convergent nub of NOD2 and TLR4 signaling pathways. This MDP-induced tolerance was impaired in Mut-Nod2 CD patients, resulting in a p38-independent TNFalpha production and an imbalance between pro- and antiinflammatory cytokines that could be partly responsible for the pathogenesis of CD.

Risk factors and characteristics of extent progression in ulcerative colitis.

BACKGROUND: The main objective was to identify risk factors for extent progression in distal ulcerative colitis. The secondary objective was to determine clinical characteristics of disease at the time of progression. METHODS: Data were obtained from a prospective database. Distal colitis was defined as disease limited to rectum and sigmoid colon (n = 178), extensive colitis as involvement of at least the descending colon (n = 179), and colitis with progression when there was a change of category from distal to extensive (n = 63). To study clinical characteristics at the time of progression, a nested case-control study was performed. RESULTS: Compared to distal colitis, colitis with progression was associated to significantly higher prevalence of extraintestinal manifestations (42.9% versus 15.5%) steroid-refractory course (28.0% versus 2.2%), requirement of thiopurines (44.3% versus 17.3%), cyclosporine (25.4% versus 1.9%), infliximab (9.5% versus 1.2%), surgery (20.6% versus 0.6%), and incidence of neoplasia (6.3% versus 0%). However, these differences appeared after disease progression. Regression analysis demonstrated that preexisting independent predictive factors for progression were younger age at diagnosis (hazard ratio [HR] 0.979 95% confidence interval [CI] 0.959-0.999) and presence of sclerosing cholangitis (HR 12.83, 95% CI 1.36-121.10). The nested case-control study showed that at the time of progression the flare was more severe in cases than in matched controls, with significant differences in markers of disease severity, therapeutic requirements, hospitalizations, and surgery. CONCLUSIONS: Patients with distal ulcerative colitis diagnosed at a younger age or with associated sclerosing cholangitis are at higher risk for progression. Disease flare associated with progression follows a severe course with high therapeutic requirements.