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Background and aims The Crohn's Disease Activity Index (CDAI) has been criticised due to heavy weighting on subjective clinical symptoms. C-reactive protein (CRP) and endoscopic lesions are objective measures of inflammation. We investigated the relationships between clinical disease activity, CRP normalisation and mucosal healing in Crohn's disease (CD). Methods The Study of Biologic and Immunomodulator Naive Patients in CD trial compared infliximab to azathioprine and to infliximab plus azathioprine in 508 CD patients. Mucosal healing was defined as the absence of mucosal ulceration at the week 26 ileocolonoscopy in a patient who had evidence of ulceration at the baseline ileocolonoscopy. Results 188 patients who had evaluable ileocolonoscopy with evidence of mucosal ulceration at baseline, CDAI scores and CRP values at baseline and week 26 were analysed. Seventy-two of 136 patients (53%) who had a CDAI<150 at week 26 achieved mucosal healing, and 38 of 90 patients (42%) achieved both CRP normalisation (CRP<0.8 mg/dL) and mucosal healing while in clinical remission. The positive predictive value (PPV) and negative predictive value (NPV) of CDAI to detect mucosal healing using 150 as a cut-off for CDAI were 65% and 53%, respectively. The PPV and NPV of CDAI to detect mucosal healing and CRP normalisation using 150 as a cut-off for CDAI were 79% and 42%, respectively. Conclusions Half the patients under azathioprine and/or infliximab in clinical remission have endoscopic and/or CRP evidence of residual active CD, whereas other patients with endoscopic and CRP normalisation have persistent clinical symptoms. Clinical symptoms as scored by CDAI are not a reliable measure of the underlying inflammation.

Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0·03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0·03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2·4, 95% CI 1·2–4·8, p=0·02) and the presence of two or more clinical risk factors including smoking (OR 2·8, 95% CI 1·01–7·7, p=0·05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0·51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0·36), respectively. Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.

Abstract Background Regulatory guidance for Crohn’s disease trials recommends coprimary efficacy end points that evaluate both symptoms and mucosal inflammation. We aimed to characterize the operating properties of commonly used disease activity assessments alone and in combination. Methods Endoscopic and clinical data were available for 129 participants from the Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease trial. Readers scored the Simple Endoscopic Score for Crohn’s Disease and the Crohn’s Disease Endoscopic Index of Severity using standardized conventions. Index reliability was determined using intraclass correlation coefficients. Index responsiveness was assessed using standardized effect sizes based upon treatment assignment. Outcomes were evaluated for optimal sensitivity to treatment effect. Results Substantial inter-rater reliability was observed when the Simple Endoscopic Score for Crohn’s Disease and Crohn’s Disease Endoscopic Index of Severity were used as continuous measures (intraclass correlation coefficient, 0.64; 95% confidence interval [CI], 0.50-0.73; and 0.62 95% CI, 0.36-0.77) compared with moderate reliability when dichotomized (0.46; 95% CI, 0.26-0.65; and 0.51; 95% CI, 0.00-0.78). The Simple Endoscopic Score for Crohn’s Disease, Crohn’s Disease Endoscopic Index of Severity, patient-reported outcome-2, and Crohn’s Disease Activity Index were similarly responsive (standardized effect size, 0.43, 95% CI, 0.05-0.81; 0.38, 95% CI, 0.0-0.76; 0.53, 95% CI, 0.15-0.91). A composite outcome of Crohn’s Disease Activity Index score <150 and Crohn’s Disease Endoscopic Index of Severity score <6 was most sensitive to treatment effect (28.9%; 95% CI, 11.0%-46.8%; P = .003). Conclusion Endoscopic indices were more reliable as continuous measures. Composite outcomes including endoscopy improved sensitivity to treatment effect. Lay Summary This study largely supports current regulatory guidance for Crohn’s disease trials recommending coprimary efficacy end points evaluating both symptoms and mucosal inflammation. Continuous endoscopic measures are most reliable and improve sensitivity to treatment effect when employed in composite outcomes.

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be “diagnostic modality driven”: for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011)

The ancient Chinese medical literature, as well as our prior clinical experience, suggests that fecal microbiota transplantation (FMT) could treat the inflammatory mass. We aimed to evaluate the efficacy and safety of multiple fresh FMTs for Crohn’s disease (CD) complicated with intraabdominal inflammatory mass. The \"one-hour FMT protocol\" was followed in all patients. Twenty-five patients were diagnosed with CD and related inflammatory mass by CT or MRI. All patients received the initial FMT followed by repeated FMTs every 3 months. The primary endpoint was clinical response (improvement and remission) and sustained clinical remission at 12 months. Secondary endpoints were improvement in size of phegmon/abscess based upon cross-sectional imaging and safety of FMT. 68.0% (17/25) and 52.0% (13/25) of patients achieved clinical response and clinical remission at 3 months post the initial FMT, respectively. The proportion of patients at 6 months, 12 months and 18 months achieving sustained clinical remission with sequential FMTs was 48.0% (12/25), 32.0% (8/25) and 22.7% (5/22), respectively. 9.5% (2/21) of patients achieved radiological healing and 71.4% (15/21) achieved radiological improvement. No severe adverse events related to FMT were observed. This pragmatic study suggested that sequential fresh FMTs might be a promising, safe and effective therapy to induce and maintain clinical remission in CD with intraabdominal inflammatory mass.

Abstract Background CALM was a randomized phase 3 trial in patients with Crohn’s disease (CD) that demonstrated improved endoscopic outcomes when treatment was escalated based on cutoffs for inflammatory biomarkers, fecal calprotectin (FC), C-reactive protein (CRP), and CD Activity Index (CDAI) remission vs CDAI response alone. The purpose of this post hoc analysis of CALM was to identify drivers of treatment escalation and evaluate the association between biomarker cutoff concentrations and endoscopic end points. Methods The proportion of patients achieving CD Endoscopic Index of Severity (CDEIS) <4 and no deep ulcers 48 weeks after randomization was evaluated according to CRP <5 mg/L or ≥5 mg/L and FC <250 μg/g or ≥250 μg/g. Subgroup analyses were performed according to disease location, and sensitivity analyses were conducted in patients with elevated CRP and/or FC at baseline. The association between endoscopic end points and biomarker cutoffs was performed using χ 2 test. Results The proportion of patients who achieved the primary end point CDEIS <4 and no deep ulcers was significantly greater for those with FC <250 µg/g (74%; P < 0.001), with an additive effect for CRP <5 mg/L. The association of FC <250 µg/g with improved endoscopic outcomes was independent of disease location, although the greatest association was observed for ileocolonic disease. Fecal calprotectin <250 µg/g, CRP <5 mg/L, and CDAI <150 gave a sensitivity/specificity of 72%/63% and positive/negative predictive values of 86%/42% for CDEIS <4 and no deep ulcers 48 weeks after randomization. Conclusion This post hoc analysis of CALM demonstrated that a cutoff of FC <250 µg/g is a useful surrogate marker for mucosal healing in CD. A post hoc analysis of a phase 3 trial in Crohn’s disease showed that a fecal calprotectin cutoff of <250 μg/g accurately classified mucosal healing at week 48 after randomization in a majority of patients.

ObjectiveLack of standardised outcomes hampers effective analysis and comparison of data when comparing treatments in fistulising perianal Crohn’s disease (pCD). Development of a standardised set of outcomes would resolve these issues. This study provides the definitive core outcome set (COS) for fistulising pCD.DesignCandidate outcomes were generated through a systematic review and patient interviews. Consensus was established via a three-round Delphi process using a 9-point Likert scale based on how important they felt it was in determining treatment success culminating in a final consensus meeting. Stakeholders were recruited nationally and grouped into three panels (surgeons and radiologists, gastroenterologists and IBD specialist nurses, and patients). Participants received feedback from their panel (in the second round) and all participants (in the third round) to allow refinement of their scores.ResultsA total of 295 outcomes were identified from systematic reviews and interviews that were categorised into 92 domains. 187 stakeholders (response rate 78.5%) prioritised 49 outcomes through a three-round Delphi study. The final consensus meeting of 41 experts and patients generated agreement on an eight domain COS. The COS comprised three patient-reported outcome domains (quality of life, incontinence and a combined score of patient priorities) and five clinician-reported outcome domains (perianal disease activity, development of new perianal abscess/sepsis, new/recurrent fistula, unplanned surgery and faecal diversion).ConclusionA fistulising pCD COS has been produced by all key stakeholders. Application of the COS will reduce heterogeneity in outcome reporting, thereby facilitating more meaningful comparisons between treatments, data synthesis and ultimately benefit patient care.

Abstract Background The POWER study (NCT03782376) evaluated efficacy and safety of a single ustekinumab intravenous (IV) reinduction dose versus placebo under continued ustekinumab subcutaneous (SC) treatment in adult patients with moderately to severely active Crohn’s disease who demonstrated a secondary loss of response to ustekinumab every 8 weeks (q8w) maintenance therapy. Methods Patients were randomly assigned 1:1 at Week 0 to ustekinumab IV reinduction (ustekinumab ∼6 mg/kg and SC placebo) or continuous maintenance (IV placebo and SC ustekinumab 90 mg q8w). Clinical and biomarker assessments occurred at Weeks 0, 8, 16, and 24 with optional ileocolonoscopy at Weeks 0 and16. The primary endpoint was clinical response (≥100-point decrease from baseline Crohn’s Disease Activity Index [CDAI] score or CDAI <150) at Week 16. Safety events were analyzed through Week 36 and serum samples were collected for pharmacokinetic analyses and anti-ustekinumab antibody detection. Results Overall, 215 patients were randomized: 108 to the IV reinduction group and 107 to the SC group. In the IV reinduction group, 49.1% achieved clinical response at Week 16 versus 37.4% in the SC group (adjusted treatment difference 11.5% [95% CI: −1.5%, 24.5%; P = .089]). Proportions of patients with endoscopic remission and improvement, normalization of inflammatory biomarkers, and improvement in IBDQ score were greater in the IV reinduction group vs the SC group. No new safety signals were identified. Conclusions Although the primary endpoint of clinical response was not met at Week 16, ustekinumab IV reinduction showed numerical improvements in objective endpoints including inflammatory biomarkers and endoscopic outcomes compared with SC maintenance therapy. Safety and immunogenicity results were consistent with the established profile of ustekinumab. Lay Summary Some patients with Crohn’s disease who respond to biologic treatment may lose response over time. The POWER study evaluated the efficacy and safety of receiving an additional intravenous dose of ustekinumab in patients who initially lost response to ustekinumab. Graphical abstract Graphical Abstract

The impact of severity and location of Crohn's disease (CD) endoscopic ulcers on endoscopic remission in patients treated with antitumor necrosis factor is poorly known. We aimed to describe the endoscopic evolution of CD lesions in a prospective cohort of patients treated with infliximab (IFX) in combo therapy. We conducted a post hoc analysis of the TAILORIX randomized controlled trial, which studied biologic-naïve patients with active CD and endoscopic ulcers receiving IFX combo therapy. Ileocolonoscopies were performed at week 0, 12, and 54. Endoscopic healing was defined as the absence of ulcers and complete endoscopic remission as CD Endoscopic Index of Severity (CDEIS) <3. Ileocolonic segments were scored separately for remission by blinded readers. A total of 122 (median disease duration: 7 months) patients were included, corresponding with 379 diseased segments. The median (IQR) CDEIS scores at week 0, 12, and 54 were 9.9 (6.1-14.4), 2.4 (0.2-4.6), and 0.2 (0.0-3.7), respectively. At weeks 12 and 54, the rates of endoscopic healing and complete endoscopic remission were 41% and 61% and 61% and 73%, respectively. Median CDEIS scores were similar among patients with deep ulcers at baseline and those with only superficial ulcers at week 12 and 54. Segmental remission rates were lower both at week 12 and 54 in the ileum compared with colonic segments (P < 0.01 all comparisons) and in the rectum (P = 0.02 and P = 0.03). In biologic-naive patients with CD treated with IFX combo therapy, the severity of endoscopic lesions at the baseline did not influence healing rates. Endoscopic remission occurs less frequently in the ileum compared with the colon.

Iron deficiency anemia (IDA) is frequently seen in inflammatory bowel disease. Traditionally, oral iron supplementation is linked to extensive gastrointestinal side effects and possible disease exacerbation. This multicenter phase-3 study tested the efficacy and safety of ferric maltol, a complex of ferric (Fe3+) iron with maltol (3-hydroxy-2-methyl-4-pyrone), as a novel oral iron therapy for IDA.MethodsAdult patients with quiescent or mild-to-moderate ulcerative colitis or Crohn's disease, mild-to-moderate IDA (9.5–12.0 g/dL and 9.5–13.0 g/dL in females and males, respectively), and documented failure on previous oral ferrous products received oral ferric maltol capsules (30 mg twice a day) or identical placebo for 12 weeks according to a randomized, double-blind, placebo-controlled study design. The primary efficacy endpoint was change in hemoglobin (Hb) from baseline to week 12. Safety and tolerability were assessed.ResultsOf 329 patients screened, 128 received randomized therapy (64 ferric maltol-treated and 64 placebo-treated patients) and comprised the intent-to-treat efficacy analysis: 55 ferric maltol patients (86%) and 53 placebo patients (83%) completed the trial. Significant improvements in Hb were observed with ferric maltol versus placebo at weeks 4, 8, and 12: mean (SE) 1.04 (0.11) g/dL, 1.76 (0.15) g/dL, and 2.25 (0.19) g/dL, respectively (P < 0.0001 at all time-points; analysis of covariance). Hb was normalized in two-thirds of patients by week 12. The safety profile of ferric maltol was comparable with placebo, with no impact on inflammatory bowel disease severity.ConclusionsFerric maltol provided rapid clinically meaningful improvements in Hb and showed a favorable safety profile, suggesting its possible use as an alternative to intravenous iron in IDA inflammatory bowel disease.