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Background Janus kinase (JAK) inhibition shows promise for treatment of patients with moderate to severe Crohn’s disease. We aimed to provide mechanistic insights into the JAK1-selective inhibitor upadacitinib through a transcriptomics substudy on biopsies from patients with Crohn's disease from CELEST. Methods Seventy-four patients consented to this optional substudy. Ileal and colonic biopsies were collected during endoscopy at screening and week 12 or 16. RNA isolated from 226 samples was analyzed by RNAseq, with additional qPCR analysis. Additional biopsies from patients with Crohn's disease receiving anti-tumor necrosis factor (anti-TNF; n = 34) and healthy controls (n = 10) were used for qPCR. Single-cell RNAseq public profiles were used to evaluate treatment effects on specific cellular subsets, associations with endoscopic improvement, and indirect comparisons with the anti-TNF-treated cohort. Results In involved areas of mucosa with endoscopic remission after upadacitinib treatment, 1156 and 76 protein-coding genes were significantly regulated (false discovery rate < 0.05) at week 12/16 in colonic and ileal biopsies, respectively (60 overlapped), compared with baseline. Upadacitinib did not significantly affect transcriptomes of noninvolved intestinal areas. CELEST patients (mostly anti-TNF-refractory) showed baseline differences in gene expression compared with a separate cohort of biologic-naïve patients. Notably, upadacitinib reversed overexpression of inflammatory fibroblast and interferon-γ effector signature markers. Conclusions Upadacitinib modulates inflammatory pathways in mucosal lesions of patients with anti-TNF-refractory Crohn's disease, including inflammatory fibroblast and interferon-γ-expressing cytotoxic T cell compartments. This substudy is the first to describe the molecular response to JAK1 inhibition in inflammatory bowel disease and differential effects relative to anti-TNF treatment. (Clinical trial identifier: NCT02365649)

Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We examined the effect of tofacitinib induction treatment on Inflammatory Bowel Disease Questionnaire (IBDQ) items in adults with moderate to severe UC. Methods Data were pooled from the randomized, 8‑week, double-blind, phase 3 OCTAVE Induction 1 and 2 studies. The IBDQ was self-administered by patients at baseline, week 4, and week 8, with higher scores indicating better health-related quality of life (HRQoL). Change from baseline in IBDQ items was analyzed for 10 mg of tofacitinib twice daily (BID) vs placebo using a linear mixed-effects model, with no multiplicity adjustment performed. Effect sizes were calculated. Subgroup analyses by tumor necrosis factor inhibitor (TNFi) experience were performed. Results Significant improvements (nominal P < 0.05) were observed in all IBDQ items with 10 mg of tofacitinib BID vs placebo at weeks 4 and 8. For the overall population, the largest treatment differences across all items were reported for “bowel movements been loose” at weeks 4 and 8, and “problem with rectal bleeding” at week 8 (mean treatment differences all 1.1; both in bowel symptoms domain). These items also showed the largest effect sizes. Treatment benefits were generally slightly numerically higher in TNFi-experienced vs TNFi-naïve patients. Conclusions Tofacitinib induction therapy improved all IBDQ items vs placebo in patients with UC, reflecting improvements in HRQoL, with greatest benefits reported in bowel symptoms domain items (Funded by Pfizer Inc; OCTAVE Induction 1 and OCTAVE Induction 2; ClinicalTrials.gov, NCT01465763 and NCT01458951, respectively).

Background and Aims Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473—an oral gut-selective pan-JAK inhibitor—from in vitro characterization through a Phase 1b study in patients with UC. Methods TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice. In a first-time-in-human study, plasma pharmacokinetics and safety were assessed after single and multiple [14 days] ascending doses administered orally to healthy subjects. The Phase 1b study randomized patients with moderately to severely active UC to receive once-daily oral TD-1473 20, 80 or 270 mg, or placebo for 28 days. Plasma and colonic tissue concentrations were measured; safety was assessed; and efficacy was evaluated by UC clinical parameters, disease-surrogate biomarkers, endoscopy, histology and colonic tissue JAK signalling. Results TD-1473 exhibited potent pan-JAK inhibitory activity in vitro. Oral TD-1473 administration to mice achieved high, biologically active colonic tissue concentrations with low plasma exposure and decreased oxazolone-induced colitis activity without reducing blood cell counts vs placebo. TD-1473 administration in healthy human subjects and patients with UC yielded low plasma exposure and was generally well tolerated; treatment in patients with UC resulted in biologically active colonic tissue concentrations and descriptive trends toward reduced clinical, endoscopic and histological disease activity vs placebo. Conclusion Gut-selective pan-JAK inhibition with TD-1473 administration resulted in high intestinal vs plasma drug exposure, local target engagement, and trends toward reduced UC disease activity. [Clinicaltrials.gov NCT02657122, NCT02818686]

Background Gadolinium-enhanced sequences are not included in the simplified Magnetic Resonance Index of Activity [sMARIA], but in the derivation of this index readers had access to these sequences. The current study aimed to validate the sMARIA without gadolinium-enhanced sequences for assessing disease activity, severity, and response to treatment in patients with Crohn’s disease. Methods We prospectively included patients with active Crohn’s disease and at least one segment with severe inflammation [ulcers] at ileocolonoscopy, who required treatment with biologic drugs. Patients were evaluated by both magnetic resonance enterography [MRE] and ileocolonoscopy at baseline and 46 weeks after initiation of medical treatment. We compared the quantification of disease activity and response to treatment with sMARIA versus with ileocolonoscopy Crohn’s Disease Index of Severity [CDEIS], considered the gold standard. Results Data from both MRE and ileocolonoscopy 46 weeks after treatment initiation were available for 39 of the 50 patients. As in the derivation study, the optimal cutoffs were sMARIA ≥1 for predicting active disease (area under the curve [AUC] 0.92) and sMARIA ≥2 for predicting the presence of ulcers at ileocolonoscopy [AUC 0.93]. In evaluating the response to treatment, the sMARIA detected endoscopic ulcer healing at the segment level [sMARIA Conclusions The sMARIA is accurate and reliable in quantifying disease activity and response to treatment in luminal Crohn’s disease, without the need for gadolinium-enhanced sequences.

Background and Aims The Observational Postmarketing Ulcerative colitis Study [OPUS] was conducted to obtain the first long-term [5 years] safety data assessing treatment with originator infliximab versus conventional therapies in patients with ulcerative colitis [UC] in real-world clinical practice. Methods The OPUS registry was a prospective, non-randomised, observational study that measured adverse events in nine prespecified categories of interest in UC patients whose treatment with either originator infliximab or conventional therapy [defined as initiation or dose-increase of corticosteroids and/or immunosuppressants] was determined by their treating physician. Results Data for 2239 patients were available: N = 1180 enrolled to conventional therapy [including N = 296 who switched to originator infliximab during follow-up] and N = 1059 enrolled to originator infliximab. Patients in the originator infliximab group, compared with the conventional therapy group, had more severe disease at baseline, based on partial Mayo score [PMS]: 46.0% of patients in the originator infliximab group had severe disease (PMS of 7–9 [out of 9]), compared with 30.5% in the conventional therapy group. In adjusted time-to-event analyses, enrolment into the originator infliximab group was associated with a higher risk of serious infection (hazard ratio = 1.98 [95% confidence interval: 1.34, 2.91; p Conclusions UC patients treated with infliximab had higher risk for serious infection, compared with conventional therapies. No new safety concerns were observed with originator infliximab in the OPUS registry. [ClinicalTrials.gov: NCT00705484.]

Background Mirikizumab (miri), an anti-IL-23p19 monoclonal antibody, demonstrated efficacy and was well-tolerated in a phase 2 randomised clinical trial in patients with moderate-to-severe ulcerative colitis (UC; NCT02589665). After 12 weeks (W) of treatment, miri was shown to down-regulate several transcripts correlated with increased UC disease activity as well as anti-TNF resistance. Here we show W52 gene expression analysis from the induction responder cohort at W12 for both miri and PBO treated patient biopsy samples to identify sustained changes in gene expression. Methods Miri-treated patients who achieved clinical response (decrease in 9-point Mayo subscore [rectal bleeding, stool frequency, endoscopy] of ≥2 points and ≥35% from baseline [BL] with either a decrease of RB subscore of ≥1 or an RB subscore of 0 or 1) or better at W12 were re-randomised to miri 200 mg administered subcutaneously (SQ) every 4 weeks or every 12 weeks through W52. Patients given placebo (PBO) in induction who achieved clinical response continued on PBO in the maintenance period. Colonic biopsies were obtained at W0, 12, and 52 from the most affected area at least 30 cm from the anal verge (miri N=31, PBO N=7). Transcript changes at W12 from BL in the PBO and miri arms were clustered into differentially expressed genes (DEGs) using the Bayesian Limma R-package. Among these DEGs, similarly expressed genes (SEGs) were identified as those which maintained their W12 expression level through W52. Results Analysis of transcript changes in W12 responders who continued to maintenance identified a profile of DEG-SEGs in responders (Fig 1A). Of these genes, 63 (70.8%) were present only in miri responders, 5 (5.6%) were present only in PBO responders, and 21 (23.6%) were present in both groups (Fig 1B, C). The magnitude of transcript changes was greater at W12, and more consistent through W52, in the group of miri responders compared to PBO responders (Fig 2). A separate cluster of DEG-SEGs correlated with to disease activity indeces (Robarts Histopathology Index [RHI], modified Mayo; both r>0.5) were shown to be sustained in the miri treated patients but not in the placebo patients. Conclusion In this limited sample of W12 PBO and miri responders, miri responders showed broader, larger, and more sustained magnitude of changes at W52 compared to PBO responders. The qualitative description of transcripts suggests a distinct molecular healing pathway associated with miri treatment, as compared to the spontaneous healing that occurred in PBO responders. A cluster of transcripts that correlated with disease activity indices was identified, demonstrating consistency across molecular, endoscopic and clinical indices of healing in UC.

Background and Aims We aimed to investigate the underlying mechanism of action of risankizumab, a monoclonal antibody targeting the IL-23 p19 subunit, previously reported to induce clinical and endoscopic remission in a randomised phase II study in patients with active Crohn’s disease. Methods Ileum and colon biopsies obtained at screening and Week 12 from a subgroup of patients [n = 106] in the risankizumab phase II study were analysed by transcriptome-wide RNA-Seq profiling. Univariate associations were assessed using linear modelling. Results By Week 12, risankizumab significantly decreased [p < 0.005] the expression of 1880 and 765 genes in the colon [false-discovery rate = 0.02] and ileum [false-discovery rate = 0.05], respectively. These genes were associated with the IL-23/IL-17 axis, Th1 pathway, innate immunity, and tissue turnover. Colonic transcriptomic profiles following risankizumab treatment reflected the transcriptomic changes observed in patients achieving endoscopic response and remission at Week 12 and were significantly different from placebo [p < 0.005]. The colonic transcriptomic profile, significantly modulated by risankizumab at Week 12, was indicative of suppression of pathways associated with epithelial biology. Furthermore, pathways associated with Crohn’s disease modulated by risankizumab treatment included second messenger-mediated signalling, immune response, lymphocyte and leucocyte activation, lymphocyte differentiation and cell–cell adhesion. Conclusions Endoscopic remission and response observed with risankizumab in patients with active Crohn’s disease was associated with significant transcriptomic changes in the colon, compared with placebo. Differentiated expression of genes associated with the IL-23/IL-17 axis was observed in the colon and ileum 12 weeks after risankizumab treatment.

[Background and Aims] Steroid-dependency occurs in up to 30% of patients with ulcerative colitis [UC]. In this setting, few drugs have demonstrated efficacy in inducing steroid-free remission. The aim of this study was to evaluate the efficacy and safety of adding granulocyte/monocyte apheresis [GMA] to oral prednisone in patients with steroid-dependent UC., [Methods] This was a randomized, multicentre, open trial comparing 7 weekly sessions of GMA plus oral prednisone [40 mg/day and tapering] with prednisone alone, in patients with active, steroid-dependent UC [Mayo score 4–10 and inability to withdraw corticosteroids in 3 months or relapse within the first 3 months after discontinuation]. Patients were stratified by concomitant use of thiopurines at inclusion. A 9-week tapering schedule of prednisone was pre-established in both study groups. The primary endpoint was steroid-free remission [defined as a total Mayo score ≤2, with no subscore >1] at Week 24, with no re-introduction of corticosteroids. [Results] In all 123 patients were included [63 GMA group, 62 prednisone alone]. In the intention-to-treat analysis, steroid-free remission at Week 24 was achieved in 13% (95% confidence interval [CI] 6–24) in the GMA group and 7% [95% CI 2–16] in the control group [p = 0.11]. In the GMA group, time to relapse was significantly longer (hazard ratio [HR] 1.7 [1.16–2.48], P = 0.005) and steroid-related adverse events were significantly lower [6% vs 20%, P < 0.05]. [Conclusions] In a randomized trial, the addition of 7 weekly sessions of GMA to a conventional course of oral prednisone did not increase the proportion of steroid-free remissions in patients with active steroid-dependent UC, though it delayed clinical relapse., This work was supported by an unrestricted research grant from Otsuka Pharmaceuticals.

Background and aims This review is the first to evaluate the burden of ulcerative colitis [UC] on patients' quality of life by synthesizing data from studies comparing scores from the SF-36® Health Survey, a generic measure assessing eight quality-of-life domains, between UC patients and matched reference samples. Methods A systematic review of the published literature identified articles reporting SF-36 domains or physical and mental component summary scores [PCS, MCS] from UC and reference samples. Burden of disease for each SF-36 domain was then summarized across studies by comparing weighted mean differences in scores between patient and reference samples with minimally important difference thresholds. Results Thirty articles met pre-specified inclusion criteria. SF-36 scores were extracted from five samples of patients with active disease, 11 samples with a mixture of disease activity, five samples of patients in clinical remission, and 13 samples of patients following proctocolectomy with ileostomy or ileal pouch-anal anastomosis, along with respective reference samples. Clinically meaningful burden was observed in samples with active or mixed disease activity [deficits: PCS = 5.6, MCS = 5.5] on all SF-36 domains except Physical Functioning. No burden was observed in samples in remission or post-surgical patients [deficits: PCS = 0.8, MCS = 0.4] except for the General Health perception domain. Conclusions Patients with active UC experience a clinically meaningful burden of disease across most aspects of quality of life. Patients with inactive UC exhibit negligible disease burden and are comparable to the general population on most quality-of-life outcomes. Thus, treatments which effectively induce and maintain remission may restore physical and mental health status.

Despite the major recent progress in the treatment of Crohn's disease [CD], there is a subset of patients in whom the disease runs an aggressive course with progressive tissue damage requiring early and repeated surgical management. Increasing evidence supports sustained and profound improvement in gastrointestinal parameters and quality of life following high-dose immunosuppressive therapy and autologous haematopoietic stem cell transplantation [AHSCT] compared to standard therapy in this context. In addition, international transplant registry data reflect the use of AHSCT in CD outside of trials in selected patients. However, AHSCT may be associated with significant treatment-related complications with risk of transplant-related mortality. In a joint initiative, the European Crohn's and Colitis Organisation [ECCO] and the European Society for Blood and Marrow Transplantation [EBMT] have produced a state-of-the-art review of the rationale, evaluation, patient selection, stem cell mobilization and transplant procedures and long-term follow up. Given the unique spectrum of issues, we recommend that AHSCT should only be performed in experienced centres with expertise in both haematological and gastroenterological aspects of the procedure. Where possible, patients should be enrolled on clinical trials and data registered centrally. Future development should be coordinated at both national and international levels.

Biosimilars of infliximab were first approved by the European Medicine Agency in 2013,1 , 2 based on pre-clinical studies on biosimilarity and on clinical data coming from two randomised controlled trials conducted in rheumatoid arthritis [RA] and ankylosing spondylitis [AS].3 , 4 Initially the European Crohn’s Colitis Organisation [ECCO] raised some caution on the use of biosimilars.5 This cautious approach was also supported by several national inflammatory bowel disease [IBD] societies5–12 [Table 1]. An insufficient understanding of the characteristics and use of biosimilars became evident in a web survey among ECCO members in the same period.13 View this table: Table 1. Available society guidelines. Since biosimilars were introduced in the EU market in early 2015, more data from IBD patients14–19 have supported the biosimilarity of biosimilar infliximab CT-P13 and the reference product, with no significant differences in terms of efficacy or safety, in either naive or switched patients in cohort studies. Importantly, a study showed clear cross-reactivity between the infliximab originator and CT-P13.20 Recently, a large nationwide Norwegian randomised controlled trial [NOR-SWITCH] on patients with immune-mediated diseases [Crohn’s disease; ulcerative colitis; psoriasis; psoriatic arthritis; RA and AS] found no differences in terms of clinical response, maintenance of remission, or adverse events in patients receiving CT-P13 compared with those receiving originator infliximab.21 Consideration of these findings22 together with a better understanding of the process of biosimilar development and regulatory approval, have contributed to a change in the perception of IBD experts, who now prescribe biosimilars with significantly more confidence.23 A task-force including Governing Board representatives and one representative from pertinent ECCO Committees performed a literature search and made relevant statements to summarise their shared position. The proposed statements were then discussed, agreed and approved in a Consensus meeting. The licensing of any biosimilar medication …

Endoscopic assessment of the presence and severity of endoscopic lesions has become an essential part of clinical trials in ulcerative colitis and Crohn's disease, for both patient eligibility and outcome measures. Variability in lesion interpretation between and within observers and the potential bias of local investigators in patient assessment have long been recognized. This variability can be reduced, although not completely removed, by independent evaluation of the examinations by experienced off-site (central) readers, properly trained in regard to lesion definition and identification, that should be removed from direct patient contact and blinded to any other clinical or study data. Adding endoscopic demonstration of active disease to eligibility criteria has the potential to reduce placebo response rates, whereas in outcome assessment it has the potential to provide a more precise estimation of the treatment effect, increasing the efficiency of the study. Central endoscopy reading is still at the beginning of its development, and the paradigms of central reading need refinement in terms of the number of readers, the process by which a final score is assigned, the selection and sequence of central readers, and the endoscopic indices of choice.

Background and Aims: This mediation modelling analysis evaluated direct and indirect effects of tofacitinib, an oral, small molecule Janus kinase inhibitor under investigation for ulcerative colitis, on patient treatment satisfaction. Methods: Data from an 8-week randomised Phase 2 trial ([NCT00787202][1]) in adults with moderate-to-severe, active ulcerative colitis receiving twice-daily tofacitinib 0.5-15 mg (n=146), or placebo (n=48) were analysed in patient-reported (n=149) and clinician-reported (n=170) outcomes-based mediation models. Binary predictor variable: treatment (pooled active treatment vs placebo). Eventual dependent variable: Week 8 patient treatment satisfaction (measured on a 5-point Likert scale). Mediators of treatment effect on satisfaction: Week 8 Inflammatory Bowel Disease Questionnaire domains (Bowel Symptoms, Emotional Health, Social Function and Systemic Symptoms) and Mayo scale domains (Stool Frequency, Rectal Bleeding, Physician's Global Assessment and Endoscopic Disease Activity) for patient-reported and clinician-reported models, respectively. Results: Overall tofacitinib indirect effect on satisfaction via Inflammatory Bowel Disease Questionnaire domains was 40.5% (P

Aims: The objective of the current study was to compare two patient assessment strategies using colonoscopy and MRI alternatively as first- and second-line examinations. Methods: Clinical data, endoscopy and magnetic resonance imaging (MRI) examinations of 100 patients diagnosed with ileocolonic Crohn’s disease (CD) performed within 1 week were blindly reviewed by 4 clinical investigators. Two investigators evaluated MRI followed by colonoscopy for 50 cases and the same examinations in reverse order for another 50 cases; the other 2 investigators evaluated the same cases switching the order of examinations. The assessments included the likelihood of the presence of inflammation, stenosis, fistula and abscess, and therapeutic recommendations. Results: Information from the first examination was considered sufficient for management in 80% of cases for MRI and only 34% of cases for colonoscopy ( p < 0.001). Adding MRI to the information from colonoscopy changed the clinicians’ confidence grade in a higher proportion of patients than adding colonoscopy to information from MRI for the diagnosis of disease activity (10 vs 4%, p = 0.03), stenosis (25 vs 9%, p < 0.001), fistula (31 vs 0%, p < 0.001) and internal abscess (27 vs 0%, p < 0.001). Indications for anti-tumour necrosis factor (TNF) therapy (51 vs 37%, F = 0.006), and surgery (12 vs 5%, F = 0.019) were more frequent after MRI than after colonoscopy as first examination. As a second examination, MRI led to change in therapy in a higher proportion of patients than colonoscopy (28 vs 8%, p < 0.001). Conclusions: In CD, information provided by MRI has a higher impact on patient management than colonoscopy and may be considered as a first-line examination for CD assessment.

It goes back to 1932 when Dr. Burrill Bernard Crohn and co-workers published their landmark paper, describing regional ileitis as a disease entity. However, clinical trial research has been developing rather slowly in luminal Crohn's disease. It took until the early seventies before the first randomized clinical trial was set up by the National Co-operative Crohn's Disease Study (NCCDS) group. Although the efforts of this group triggered a first wave of clinical trials in Crohn's disease, the lack of guidelines for conducting a clinical trial in this research area resulted in a variety of study designs and much criticism. Besides having a rather small sample size and a short follow-up time, they were often characterized by vague and subjective assessment of disease activity and treatment response. Following the advent of a new and very potent drug class in the late nineties, the anti-TNF agents, investigators started to re-think their study protocols and the first guidelines were set up by the regulatory authorities. Over the last 15years, clinical trials in luminal Crohn's disease have been evolving significantly. Inclusion criteria have been shifting from clinical scores such as Crohn's Disease Activity Index (CDAI) to more objective disease activity parameters such as biomarkers (C-reactive protein and faecal calprotectin) and endoscopic lesions. Primary endpoints have been developing from clinical response to corticosteroid-free remission and more ambitious end-points such as mucosal healing. In this paper, we will give a historical overview on clinical trials in luminal Crohn's disease, before and within the biologic era, and provide insight into how they have shaped our current understanding of trial designs in Crohn's disease.

Anti-TNF agents are often reserved for patients with severe Crohn's disease (CD).We explored the predictive value of baseline disease activity and C-reactive protein (CRP) for disease course, adalimumab efficacy for remission (induction and maintenance) in patients with moderate and severe CD, and adalimumab efficacy in moderate CD by CRP category.Post hoc analyses of remission data were performed for all randomized patients from induction (CLASSIC I) and maintenance (CHARM, EXTEND) adalimumab trials in patients with moderate (CDAI≤300) or severe (CDAI300) CD, and in high (≥10 mg/L) or low (10 mg/L) CRP moderate CD subgroups. Placebo-treated CHARM patients were evaluated for disease activity over time and time to CD-related hospitalization, by baseline disease severity and CRP.Moderate CD patients had the highest clinical remission rate and largest treatment effect size compared with placebo at week 4 after 160/80 mg induction (46.3% adalimumab, 17.4% placebo; versus 22.9%, 3.6% for severe patients). Moderate-CD/high-CRP patients had the most pronounced efficacy (57.1% adalimumab, 6.7% placebo; versus 40.7%, 20.0% for lower CRP group). Adalimumab maintenance treatment (40 mg every-other-week) achieved superior remission versus placebo at one year in moderate (32.9% versus 13.7%) and severe (27.2% versus 7.5%) cohorts. Among moderate patients, efficacy was similar by CRP category. Moderate-CD/high-CRP placebo-treated patients experienced disease activity and hospitalization rates at week 56 of CHARM approaching those of severe CD patients.This analysis suggests that moderate CD patients can be treated effectively with adalimumab, and supports using CRP to identify moderate CD patients at greatest risk of disease progression.

International audience; The management of patients with IBD requires evaluation with objective tools, both at the time of diagnosis and throughout the course of the disease, to determine the location, extension, activity and severity of inflammatory lesions, as well as, the potential existence of complications. Whereas endoscopy is a well-established and uniformly performed diagnostic examination, the implementation of radiologic techniques for assessment of IBD is still heterogeneous; variations in technical aspects and the degrees of experience and preferences exist across countries in Europe. ECCO and ESGAR scientific societies jointly elaborated a consensus to establish standards for imaging in IBD using magnetic resonance imaging, computed tomography, ultrasonography, and including also other radiologic procedures such as conventional radiology or nuclear medicine examinations for different clinical situations that include general principles, upper GI tract, colon and rectum, perineum, liver and biliary tract, emergency situation, and the postoperative setting. The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas such as the comparison of diagnostic accuracy between different techniques, the value for therapeutic monitoring, and the prognostic implications of particular findings.

Background and aims Patients' and physicians' perceptions of ulcerative colitis and its management are important for developing and guiding appropriate therapies. This study explored national differences in patients' and physicians' experiences, expectations, and beliefs about ulcerative colitis. Methods Structured, cross-sectional, online surveys evaluating various indices were completed by 775 adult patients with ulcerative colitis and 475 physicians actively managing ulcerative colitis patients from France, Germany, Ireland, Spain, the United Kingdom, and Canada. Results Patients' classification of their symptom severity differed across countries (mild, 16%–45%; moderate, 46%–58%; severe, 4%–36%). Expectations of disease control also varied, with 26% (Ireland) to 65% (Spain) describing that remission realistically involves “living without symptoms.” Within each country, more patients (45%–69%) than physicians (28%–45%) considered ulcerative colitis symptoms to affect patients' quality of life. Mean number of patient-reported flares during the past year ranged from 2.5 in Ireland to 8.0 in France. Self-reported adherence with oral 5-aminosalicylic acid (during remission) was highest in Spain (91% vs 50%–73% across other countries). Spanish patients were more likely to self-adjust their medications (54% vs 2%–5%), but reported the most dissatisfaction with therapy (42% vs 9%–27%). Irish patients were least likely to arrange physician/specialist nurse visits (14% vs 36%–49%) and least open to discussion of their condition. Conclusions Important national differences in ulcerative colitis patients' attitudes and perceptions were observed, which may help physicians improve patient care based on country-specific needs and influence self-assessments in clinical trials. The results suggest a need for structured patient education to improve adherence and outcomes.

Background In patients treated with TNF-antagonists, incident cases of tuberculosis (TB) after a negative screening have been reported, leading to the suggestion that improved TB testing is necessary. Aim The aim of the current study is to establish the incidence of TB and its characteristics in patients with inflammatory bowel disease (IBD) under TNF antagonists to design improved prevention strategies. Methods IBD patients from a single center treated with anti-TNF therapy between January 2000 and September 2011 were identified through a database that prospectively records clinical data, treatments and adverse events. Results During the study period 423 patients received anti-TNF therapy. Screening for latent TB infection (LTBI) previous to anti-TNF treatment was positive in 30 patients (6.96%). Seven patients (1.65%) developed TB while under anti-TNF treatment. Six patients (five under immunosuppressant treatment) had a negative LTBI screening. TST was positive in one patient not receiving immunosuppressants, and was treated with isoniazid before starting anti-TNF therapy. In 4 patients TB was diagnosed within the first 16 weeks after starting anti-TNF therapy. Three cases had pulmonary TB and 4 extrapulmonary disease. Conclusions In the IBD population under study, incidence of TB infection associated with anti-TNF therapy is higher than that reported in controlled trials and occurs early after treatment initiation. False negative results of LTBI despite appropriate measures may occur, suggesting that more effective screening strategies are needed.

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).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).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, P0.001; r = 0.80 P0.001, 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, P0.001).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.

In the original article, author Marjolijn Duijvestein's first and surnames were incorrectly spelt. This has now been corrected.

Background: The present study aimed at assessing whether psychological factors, specifically psychopathology and personality, together with clinical and sociodemographic factors, were independent predictors of quality of life (QoL) in patients with inflammatory bowel disease (IBD). Methods: A cohort of 147 outpatients with IBD was enrolled in the study. Clinical and sociodemographic variables were recorded. QoL was assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ); personality traits were assessed by means of the Temperament and Character Inventory; and psychopathology was evaluated by the Hospital Anxiety and Depression Scale. To explore the relation of variables on the QoL, univariate analyses were performed for each variable. Factors statistically significant at these analyses were included in a multiple linear regression analysis with dimensional and global IBDQ scores as dependent variables. Results: Some clinical and psychological factors were related with QoL, but regression analysis showed that disease activity and psychological distress were the strongest predictors of QoL impairment. Personality traits do not play a significant role in QoL. Conclusions: The presence of psychological distress in IBD patients contributes to poor QoL, along with IBD clinical activity. Controlling and minimizing the symptoms of the disease, along with identification and treatment of psychopathology, should become integral aspects of IBD care to improve QoL of these patients. (Inflamm Bowel Dis 2008)

by gest on N ovem er 3, 2016 ://ecco-jcordjournals.org/ a Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University Vienna, Vienna, Austria b Department of Gastroenterology, John Radcliffe Hospital, Oxford, United Kingdom c Department of Gastroenterology, Venizeleio General Hospital, Heraklion, Crete, Greece d Department of Gastroenterology, Federal University of Parana, Curitiba, Brazil e 2nd Department of Medicine, Semmelweis University, Budapest, Hungary f Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada g Department of Gastroenterology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands h Department of Hepatogastroenterology, Lariboisiere Hospital, Paris, France i Department of Internal Medicine and Gastroenterology, Waldfriede Hospital, Berlin, Germany j Albert Einstein Jewish Hospital, Sao Paulo, Brazil k Department of Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland l Department of Gastroenterology, Hospital Clinic Barcelona, Barcelona, Spain m Department of Gastroenterology, Centre Hospitalier Universitaire de Liege, Liege, Belgium n Centre Hospitalier Regional Universitaire de Lille, Lille, France o Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, Canada p Department of Medicine, University of Western Ontario, London, Ontario, Canada q Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada r Robarts Research Institute, University of Western Ontario, London, Ontario, Canada s Denis Diderot-Paris 7 University, Paris, France t IDIBAPS, Barcelona, Spain u CIBERehd, Barcelona, Spain v Universite Lille Nord de France, Lille, France

To advance in the assessment of therapeutic interventions for diseases that progress slowly but that lead ultimately to permanent disability, such as multiple sclerosis, rheumatoid arthritis or Crohn’s disease [CD], it is essential to evaluate the disease-modifying effects of available treatments. It is also necessary to separate these long-term effects from the short-term effects on symptoms that these treatments may afford. This separation of improvement in symptoms from change in primary disease progression can be difficult. In clinical trials, the measure of the effects of a particular therapeutic intervention is commonly done using indices. The majority of indices that have been developed for assessment of CD are measures of the severity of inflammatory activity, including evaluations based on symptoms and biomarkers [Crohn’s Disease Activity Index [CDAI]],1 endoscopy [Crohn’s Endoscopic Index of Severity [CDEIS]],2 or radiology [Magnetic Resonance Index of Activity [MaRIA]].3 Nevertheless, these are not indices reflecting purely inflammatory activity; each of these indices may be influenced by irreversible damage in the absence of active inflammation; for example, CDAI may increase due to bile salt–induced diarrhoea after ileal resection, CDEIS may increase due to presence of scars or fixed stenotic lesions, and MaRIA may increase due to persistent fibrotic thickening of the bowel wall. This may be among the reasons contributing to higher remission and response rates in early CD with the use … Department of Gastroenterology, Hospital Clinic de Barcelona, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 932275418; e-mail: jpanes{at}clinic.cat

Dear Editor, We thank Drs. Selinger, Leong and McLaughlin for their interest and insightful comments on our work. Their previous study on patients’ understanding and preference on methods of conveying statistical information is truly a pioneering work on this topic in the area of inflammatory bowel disease. The study shows the preference of patients for relative risk reduction (RR) over optical illustrations such as Cates Plots (CP) …

Background: Tofacitinib, a novel oral Janus kinase inhibitor being investigated as a targeted immunomodulator, demonstrated dose-dependent efficacy for induction of clinical response and remission in patients with active ulcerative colitis (UC) in a Phase 2 randomised controlled trial (Clinicaltrials.gov NCT00787202; Pfizer Inc A3921063). Reported here is the effect of tofacitinib on patient-reported outcomes (PROs), including aspects of health-related quality of life (HRQoL) and patient preference for study medication, in the same patient population. Methods: Patients ( 18 years of age, n = 194) with active UC (total of full Mayo score 6 12 points and moderately-toseverely active disease on sigmoidoscopy) were randomised in a 2:2:2:3:3 ratio to receive twice daily (BID) oral tofacitinib 0.5mg (n = 31), 3mg (n = 33), 10mg (n = 33) or 15mg (n = 49) or placebo (n = 48) for 8 weeks. PROs included the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Inflammatory Bowel Disease Patient-Reported Treatment Impact (IBD PRTI) questionnaire. Relationships were assessed with Pearson correlation coefficients, logistic regression for binary outcomes and linear regression for continuous outcomes. Results: At Week 8 mean IBDQ total scores improved relative to baseline across all 5 treatment groups (baseline range 123.2 134.5; Week 8 range 149.6 175.4); improvement was significantly greater for tofacitinib 15mg BID vs. placebo (mean ± std dev: 50.7±35.6 vs. 27.8±29.8, P= 0.001). At Week 8 patients receiving tofacitinib 15mg BID had an odds ratio of 4.18 (95%CI: 1.75 10.02; P< 0.001) to achieve an IBDQ response ( 16-point improvement) and an odds ratio of 5.23 (95%CI, 2.14 12.75; P< 0.001) to achieve IBDQ remission (total IBDQ score of 170) relative to placebo-treated patients. At Week 8, IBDQ total score significantly correlated with the full Mayo score (r = 0.62, P< 0.0001) and Mayo endoscopy subscore (r = 0.46, P< 0.0001). For the three PRTI questions (satisfaction, preference, willingness), at Week 8 the majority of patients receiving tofacitinib 15mg BID reported being “satisfied” or “extremely satisfied” with the drug received, definite preference for the study drug, and definite willingness to use the study drug again. Patients achieving endoscopic remission (Mayo endoscopy score of 0) had significantly more favourable (P< 0.05) IBDQ scores and PRTI scores than those not achieving endoscopic remission. Conclusions: Short-term treatment with oral tofacitinib was associated in patients with moderately-to-severely active UC with dose-dependent improvement of HRQoL and in patient preference for the study medication. The results complement reported efficacy and safety data from the same trial.

Class I alcohol dehydrogenase (ADH) phenotypes have been studied by starch gel electrophoresis and activity analysis in liver tissue obtained at necropsy from 61 non-alcoholic subjects with normal liver (controls), and in biopsies from 60 chronic alcoholics with liver disease and from 24 subjects with non-alcoholic liver disease. Twenty-three per cent of controls exhibited the ADH22−1 phenotype, which represents the highest frequency for atypical ADH found in a Caucasian population. Both alcoholic and non-alcoholic patients with liver disease showed a lower frequency of the atypical phenotype (6.6% and 8.8%, respectively). No differences in the ADH2 locus were detected among groups of patients with different severity of alcoholic and non-alcoholic liver disease.The allele frequencies of the ADH3 locus for the controls (ADH31 = 0.63, ADH32 = 0.37) are common to those of other Caucasian populations. Similar ADH3 allele frequencies were observed in patients with alcoholic and non-alcoholic liver disease. Discrepancies between the various phenotyping and genotyping studies now known for several populations suggest that local differences may exist in the distribution of the ADH polymorphism in even geographically close regions, and that the effect of ADH polymorphism on vulnerability towards alcohol may not be identical in different populations.

The Publisher and Authors regret the omission of the author (Janneke van der Woude) from the …