An expert consensus to standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Crohn's disease.

BACKGROUND: Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti-fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD. AIM: To standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Chron's disease. METHODS: An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting. RESULTS: Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre-stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post-prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24-48 weeks is considered the appropriate endpoint in pharmacological trials. CONCLUSIONS: Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design.

Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn's disease.

BACKGROUND: There are limited data to inform positioning of agents for treating moderate-severe Crohn's disease (CD). AIM: We assessed comparative efficacy and safety of first-line (biologic-naïve) and second-line (prior exposure to anti-tumour necrosis factor [TNF]-α) agents) biologic therapy for moderate-severe CD, through a systematic review and network meta-analysis, and appraised quality of evidence (QoE) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. METHODS: We identified randomised controlled trials (RCTs) in adults with moderate-severe CD treated with approved anti-TNF agents, anti-integrin agents and anti-IL12/23 agents, first-line or second-line, and compared with placebo or another active agent. Efficacy outcomes were induction and maintenance of clinical remission; safety outcomes were serious adverse events and infections. Network meta-analyses were performed, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities. RESULTS: No head-to-head trials were identified. In biologic-naïve patients, infliximab (SUCRA,0.93) and adalimumab (SUCRA,0.75) were ranked highest for induction of clinical remission (moderate QoE). In patients with prior anti-TNF exposure, adalimumab (SUCRA, 0.91; low QoE, in patients with prior response or intolerance to anti-TNF agents) and ustekinumab (SUCRA, 0.71) were ranked highest for induction of clinical remission. In patients with response to induction therapy, adalimumab (SUCRA, 0.97) and infliximab (SUCRA, 0.68) were ranked highest for maintenance of remission. Ustekinumab had lowest risk of serious adverse events (SUCRA, 0.72) and infection (SUCRA, 0.71; along with infliximab, SUCRA, 0.83) in maintenance trials. CONCLUSION: Indirect comparisons suggest that infliximab or adalimumab may be preferred first-line agents, and ustekinumab a preferred second-line agent, for induction of remission in patients with moderate-severe CD. Head-to-head trials are warranted.

Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy.

BACKGROUND: In Phase 3 studies of ustekinumab, a fully human monoclonal IL-12/23p40 antibody approved for moderate-to-severe Crohn's disease, patients entered a long-term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM-UNITI maintenance are reported. METHODS: UNITI-1 (TNF-antagonist failures) and UNITI-2 (conventional therapy failures) patients (N = 1281) entered IM-UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose-adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8-32). All Week 44 completers could enter the long-term extension without further dose adjustment. Placebo patients discontinued following study unblinding. RESULTS: A total of 718 patients (all treated) entered the long-term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient-years) were similar among all placebo and ustekinumab patients (Week 0-96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed. CONCLUSIONS: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

High body mass index is associated with increased risk of treatment failure and surgery in biologic-treated patients with ulcerative colitis.

BACKGROUND: Though pharmacokinetic studies suggest accelerated biologic drug clearance with increasing body weight, evidence of obesity's impact on clinical outcomes in biologic-treated patients with ulcerative colitis (UC) is inconsistent. AIM: To evaluate the impact of obesity on real world response to biological therapy in patients with UC. METHODS: In a single-centre retrospective cohort study between 2011-2016 of biologic-treated patients with UC, we evaluated treatment response by baseline body mass index (BMI). Primary outcome was treatment failure (composite outcome of IBD-related surgery/hospitalisation or treatment modification including dose escalation, treatment discontinuation or addition of corticosteroids); secondary outcomes were risk of IBD-related surgery/hospitalisation and endoscopic remission. We conducted multivariate Cox proportional hazard analyses to evaluate the independent impact of BMI on clinical outcomes. Stratified analysis by weight-based regimens (infliximab) or fixed-dose regimens (adalimumab, golimumab, vedolizumab, certolizumab pegol) was performed. RESULTS: We included 160 biologic-treated UC patients (50% males, 55% on infliximab) with median (IQR) age 36 y (26-52) and BMI 24.3 kg/m2 (21.4-28.7). On multivariate analysis, each 1 kg/m2 increase in BMI was associated with 4% increase in the risk of treatment failure (adjusted hazard ratio [aHR], 1.04 [95% CI, 1.00-1.08]) and 8% increase in the risk of surgery/hospitalisation (aHR, 1.08 [1.02-1.14]). The effect on treatment failure was seen in patients on weight-based dosing regimens or fixed-dose therapies. CONCLUSION: BMI is independently associated with increased risk of treatment failure in biologic-treated patients with UC, independent of dosing regimen.

Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis.

BACKGROUND: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. AIMS: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. RESULTS: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29-0.92], P = 0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR = 1.17 [95% CI 1.08-1.26], P < 0.0001, per 10% increase in corticosteroid use). CONCLUSIONS: Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.

Reliability of histologic assessment in patients with eosinophilic oesophagitis.

BACKGROUND: The validity of the eosinophilic oesophagitis (EoE) histologic scoring system (EoEHSS) has been demonstrated, but only preliminary reliability data exist. AIM: Formally assess the reliability of the EoEHSS and additional histologic features. METHODS: Four expert gastrointestinal pathologists independently reviewed slides from adult patients with EoE (N = 45) twice, in random order, using standardised training materials and scoring conventions for the EoEHSS and additional histologic features agreed upon during a modified Delphi process. Intra- and inter-rater reliability for scoring the EoEHSS, a visual analogue scale (VAS) of overall histopathologic disease severity, and additional histologic features were assessed using intra-class correlation coefficients (ICCs). RESULTS: Almost perfect intra-rater reliability was observed for the composite EoEHSS scores and the VAS. Inter-rater reliability was also almost perfect for the composite EoEHSS scores and substantial for the VAS. Of the EoEHSS items, eosinophilic inflammation was associated with the highest ICC estimates and consistent with almost perfect intra- and inter-rater reliability. With the exception of dyskeratotic epithelial cells and surface epithelial alteration, ICC estimates for the remaining EoEHSS items were above the benchmarks for substantial intra-rater, and moderate inter-rater reliability. Estimation of peak eosinophil count and number of lamina propria eosinophils were associated with the highest ICC estimates among the exploratory items. CONCLUSION: The composite EoEHSS and most component items are associated with substantial reliability when assessed by central pathologists. Future studies should assess responsiveness of the score to change after a therapeutic intervention to facilitate its use in clinical trials.

Physicians' perspective on the clinical meaningfulness of inflammatory bowel disease trial results: an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) survey.

BACKGROUND: Several novel compounds are being developed for inflammatory bowel diseases (IBD). In addition, biosimilar drugs are being approved. An increasing number of head-to-head, superiority and non-inferiority trials in patients with IBD are expected in the future. The clinical relevance of the magnitude of the effect size is often debated. AIM: To better understand physicians' perspectives on the clinical meaningfulness of IBD trial results. METHODS: We conducted an online survey among all IOIBD (International Organization for the Study of Inflammatory Bowel Diseases) members, asking their opinion on the clinical relevance of the results of IBD trials. RESULTS: Forty-six IOIBD members responded to the survey (52.3%). In biologic-naïve ulcerative colitis (UC) and Crohn's disease (CD) patients, most of the participants considered a 15% difference with placebo for clinical remission and endoscopic remission to be clinically relevant. In head-to-head trials, most of participants considerer a 10% difference between groups for clinical remission and endoscopic remission to be clinically relevant. Half of respondents considered 10% to be an adequate margin in non-inferiority trials. In bioequivalence studies, most of the participants considered adequate a ± 5% difference between a biosimilar and the originator for pharmacokinetic parameters, efficacy, safety and immunogenicity. Regarding safety, the difference between two drugs considered clinically relevant varied from 1% to 5%, depending on the type of adverse event. CONCLUSIONS: This is the first survey exploring how physicians perceive IBD trial results, providing an estimation of the magnitude of the difference between treatment arms that may directly influence clinical practice.

Long-term safety of adalimumab in clinical trials in adult patients with Crohn's disease or ulcerative colitis.

BACKGROUND: Adalimumab is used to treat moderate to severe Crohn's disease (CD) and ulcerative colitis (UC) when conventional therapies fail. AIM: To update long-term adalimumab safety from CD and UC trials; the previous report was CD only, 3160 patients/3402 patient-years (PYs). METHODS: Treatment-emergent adverse events (AEs; first dose to 70 days after last dose/December 31, 2015) in adults in phase 2/3 and 3/3b trials and open-label extensions were coded using Medical Dictionary for Regulatory Activities (MedDRA-v18.1). Rates were assessed as events/100 (E/100 PYs). RESULTS: The database (16 trials; CD, N = 3606; UC, N = 1739) represented 4145 and 3397 PYs of exposure, respectively. For CD, incidences of any AEs with adalimumab were 60.8%-65.1%, depending on dose, and 71.5% with placebo; for UC, the incidences were 53.5%-54.8% and 56.1%, respectively. Rates of any AEs (CD, 605 E/100 PYs; UC, 361 E/100 PYs), serious AEs (CD, 36.1 E/100 PYs; UC, 18.9 E/100 PYs), and malignancies (CD, 1.2 E/100 PYs; UC, 1.0 E/100 PYs) were similar between current and prior analyses. Apparent rate of opportunistic infections was lowered to 0.3 and 0.2 E/100 PYs for CD and UC, respectively, by recent MedDRA changes excluding oral candidiasis and tuberculosis. Standardised incidence ratios for malignancies were similar to the general population (CD, 1.45 [95% CI, 0.90-2.22]; UC, 1.36 [95% CI, 0.84-2.07]). Demyelinating disorders were uncommon (CD, 0.1 E/100 PYs; UC, <0.1 E/100 PYs). CONCLUSIONS: Patients with moderately to severely active Crohn's disease or ulcerative colitis continued to experience acceptable safety with adalimumab, without new safety signals.

Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease.

BACKGROUND: Therapeutic drug monitoring may optimize therapy for Crohn's disease (CD). AIM: To use a population pharmacokinetic model that accounts for the time-varying nature of covariates to simulate certolizumab pegol (CZP) concentrations to evaluate the exposure-response relationship for CZP in Crohn's disease. METHODS: Adults (N = 2157) with Crohn's disease were treated with CZP in nine clinical trials. Simulated CZP concentrations were compared to outcomes at weeks 6 and 26, including Crohn's disease activity index (CDAI) response (decrease from baseline ≥ 100 points), remission (CDAI ≤ 150), C-reactive protein (CRP) ≤ 5 mg/L, faecal calprotectin (FC) ≤ 250 µg/g, and a composite endpoint of CDAI ≤ 150 and FC ≤ 250 µg/g. Multivariable analyses identified covariates associated with outcomes and receiver operating characteristic analyses determined optimal CZP concentrations. RESULTS: CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical response, remission, CRP ≤ 5 mg/L or FC ≤ 250 µg/g at week 6 than without. In multivariable analyses, higher CZP concentrations at week 6 were associated with the composite outcome at weeks 6 and 26 (P < .001). Although the exposure-response relationship varied among patients, approximate CZP concentrations of at least 36.1 µg/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 µg/mL (PPV 28.0% and NPV 90.4%) at weeks 6 and 12 were associated with weeks 6 and 26 outcomes. CONCLUSIONS: An exposure-response relationship was apparent for CZP in Crohn's disease and achieving higher CZP concentrations may increase the likelihood of attaining efficacy outcomes, but this remains to be evaluated prospectively.

Systematic review with network meta-analysis: first- and second-line pharmacotherapy for moderate-severe ulcerative colitis.

BACKGROUND: There are limited data to inform positioning of agents for treating moderate-severe ulcerative colitis (UC). AIM: To assess comparative efficacy and safety of different therapies as first-line (biologic-naïve) and second-line (prior exposure to anti-tumour necrosis factor(TNF)-α) agents for moderate-severe UC, through a systematic review and network meta-analysis, and appraise quality of evidence (QoE) using grading of recommendations, assessment, development and evaluation (GRADE) approach. METHODS: We identified randomised controlled trials (RCTs) in adults with moderate-severe UC treated with anti-TNF agents, anti-integrin agents and janus kinase (JAK) inhibitors, as first-line or second-line agents, and compared with placebo or another active agent. Efficacy outcomes were induction/maintenance of remission and mucosal healing; and safety outcomes were serious adverse events and infections. Network meta-analyses were performed, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities. RESULTS: In biologic-naïve patients (12 trials, no head-to-head comparisons), infliximab and vedolizumab were ranked highest for induction of clinical remission (infliximab: odds ratio [OR], 4.10 [95% confidence intervals [CI], 2.58-6.52]; SUCRA,0.85; vedolizumab:SUCRA,0.82) and mucosal healing (infliximab:SUCRA,0.91; vedolizumab:SUCRA,0.81) (moderate QoE). In patients with prior anti-TNF exposure (4 trials, no head-to-head comparisons), tofacitinib was ranked highest for induction of clinical remission (OR, 11.88 [2.32-60.89]; SUCRA, 0.96) and mucosal healing (moderate QoE). Differences in trial design limited comparability of trials of maintenance therapy for efficacy. Vedolizumab was ranked safest in terms of serious adverse events (SUCRA, 0.91), and infection (SUCRA, 0.75) in maintenance trials. CONCLUSIONS: Infliximab and vedolizumab are ranked highest as first-line agents, and tofacitinib is ranked highest as second-line agent, for induction of remission and mucosal healing in patients with moderate-severe UC, based on indirect comparisons. Head-to-head trials are warranted to inform clinical decision-making with greater confidence.

Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis.

BACKGROUND: High concentration mesalazine formulations are more convenient than conventional low concentration formulations for the treatment of ulcerative colitis (UC). AIM: To compare the efficacy and safety of 1600 mg and 400 mg tablet mesalazine formulations. METHODS: Patients with mild-to-moderate active UC (Mayo Clinic Score >5; N=817) were randomised to 3.2 g of oral mesalazine, administered as two 1600 mg tablets once, or four 400 mg tablets twice daily. We hypothesised that treatment with the 1600 mg tablet was non-inferior (within a 10% margin) to the 400 mg tablet for induction of clinical and endoscopic remission at week 8. Open-label treatment with the 1600 mg tablet continued for 26-30 weeks based on induction response. Predictors of treatment response were also explored. RESULTS: At week 8, remission occurred in 22.4% and 24.6% of patients receiving the 1600 mg and 400 mg tablets, respectively (absolute difference -2.2%, 95% CI: -8.1% to 3.8%, non-inferiority P=.005). Endoscopic and histopathologic disease activity, leucocyte concentration and age were significantly associated with clinical remission (P=.022, .042, .014 and .023, respectively). At week 38, 43.9% (296/675) of patients who continued treatment with the 1600 mg formulation were in remission, including 70.3% (142/202) of patients who received a reduced dose of mesalazine (1.6 g/d). The overall incidence of serious adverse events was low. CONCLUSIONS: Induction therapy with 3.2 mg mesalazine using two 1600 mg tablets once-daily was statistically and clinically non-inferior to a twice-daily regimen using four 400 mg tablets (NCT01903252).

The development of a magnetic resonance imaging index for fistulising Crohn's disease.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. AIMS: To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. METHODS: A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. RESULTS: Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. CONCLUSIONS: Although "almost perfect" intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument.

Review article: moving towards common therapeutic goals in Crohn's disease and rheumatoid arthritis.

BACKGROUND: Crohn's disease (CD) and rheumatoid arthritis are chronic, progressive and disabling conditions that frequently lead to structural tissue damage. Based on strategies originally developed for rheumatoid arthritis, the treatment goal for CD has recently moved from exclusively controlling symptoms to both clinical remission and complete mucosal healing (deep remission), with the final aim of preventing bowel damage and disability. AIM: To review the similarities and differences in treatment goals between CD and rheumatoid arthritis. METHODS: This review examined manuscripts from 1982 to 2016 that discussed and/or proposed therapeutic goals with their supportive evidence in CD and rheumatoid arthritis. RESULTS: Proposed therapeutic strategies to improve outcomes in both rheumatoid arthritis and CD include: (i) evaluation of musculoskeletal or organ damage and disability, (ii) tight control, (iii) treat-to-target, (iv) early intervention and (v) disease modification. In contrast to rheumatoid arthritis, there is a paucity of disease-modification trials in CD. CONCLUSIONS: Novel therapeutic strategies in CD based on tight control of objective signs of inflammation are expected to change disease course and patients' lives by halting progression or, ideally, preventing the occurrence of bowel damage. Most of these strategies require validation in prospective studies, whereas several disease-modification trials have addressed these issues in rheumatoid arthritis over the last decade. The recent approval of new drugs in CD such as vedolizumab and ustekinumab should facilitate initiation of disease-modification trials in CD in the near future.

Systematic review with meta-analysis: placebo rates in induction and maintenance trials of Crohn's disease.

BACKGROUND: Minimising placebo response is essential for drug development. AIM: To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates. METHODS: MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates. RESULTS: In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16-21%] and 28% (95% CI 24-32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25-39%) and 26% (95% CI 19-35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics. CONCLUSIONS: Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease.

Review article: dose optimisation of infliximab for acute severe ulcerative colitis.

BACKGROUND: Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. AIM: To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. METHODS: We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case-controlled studies. RESULTS: Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. CONCLUSIONS: Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority.

Systematic review with meta-analysis: recurrence of Crohn's disease after total colectomy with permanent ileostomy.

BACKGROUND: Subtotal or total colectomy or proctocolectomy with permanent ileostomy (TC-PI) may be a treatment option for medically refractory colonic Crohn's disease (CD). AIM: To perform a systematic review and meta-analysis to evaluate the rate, risk factors and outcomes of CD recurrence after TC-PI. METHODS: In a systematic review ending 31 March 2016, we identified 18 cohort studies (1438 adults) who underwent TC-PI for colonic CD (median follow-up, 7.4 years; interquartile range, 5.3-9.0). We estimated pooled rates [with 95% confidence interval (CI)] of clinical and surgical recurrence, and risk factors for disease recurrence. RESULTS: On meta-analysis, the risk of clinical recurrence after TC-PI was 28.0% (95% CI, 21.7-35.3; 14 studies, 260/1004 patients), with a 5 and 10-year median cumulative rate of 23.5% (range, 7-35) and 40% (range, 11-60) respectively. The risk of surgical recurrence was 16.0% (95% CI, 11.1-22.7; 10 studies; 183/1092 patients), with a 5 and 10-year median cumulative rate of 10% (range, 3-29) and 18.5% (range, 14-34) respectively. The risk of clinical and surgical recurrence in patients without ileal disease at baseline was 11.5% (95% CI, 7.7-16.8) and 10.4% (95% CI, 4.5-22.5) respectively. History of ileal disease was associated with 3.2 times higher risk of disease recurrence (RR, 3.2; 95% CI, 1.8-5.6). Other inconsistent risk factors for disease recurrence were penetrating disease and young age at disease onset. CONCLUSIONS: Small bowel clinical recurrence occurs in about 28% of patients after total colectomy with permanent ileostomy for colonic Crohn's disease. Disease recurrence risk is 3.2 times higher in patients with history of ileal disease, and continued medical therapy may be advisable in this population. In patients without ileal inflammation at surgery, continued endoscopic surveillance may identify asymptomatic disease recurrence to guide therapy.

Effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in patients with Crohn's disease or ulcerative colitis who had failed conventional therapy.

BACKGROUND: Adalimumab is approved for use in patients with moderate to severe Crohn's disease (CD) or ulcerative colitis (UC) who have not achieved disease control with conventional therapies including corticosteroids and/or immunomodulators (IMM). AIM: To analyse six studies that examined efficacy, pharmacokinetics and safety of combination IMM/adalimumab therapy, compared with adalimumab monotherapy in patients with inadequate disease control on conventional therapy. METHODS: Patients with moderate to severe CD or UC from randomised, double-blind, placebo-controlled trials were analysed. Adalimumab was added to background therapy; patients were categorised as receiving adalimumab monotherapy (CD induction, n = 245, maintenance, n = 185; UC induction, n = 213, maintenance, n = 157) or combination therapy (CD induction, n = 139, maintenance, n = 139; UC induction, n = 140, maintenance, n = 100) according to baseline immunomodulator use. Efficacy was reported for the intent-to-treat populations from each study, with remission defined as CD activity index <150 for CD and Mayo score ≤2 with no subscore >1 for UC. Safety was assessed via adverse events. RESULTS: The proportions of patients achieving remission were similar for adalimumab monotherapy and immunomodulator combination therapy in all studies. Median adalimumab concentrations at week 4 or 8 were numerically but not significantly higher with adalimumab combination therapy vs. monotherapy in the CD and UC studies respectively. Incidence and rate of adverse events was similar for adalimumab monotherapy and combination therapy. CONCLUSIONS: Post hoc analysis of six randomised, controlled trials demonstrated no efficacy benefits with immunomodulator/adalimumab combination therapy, compared with adalimumab monotherapy in CD and UC patients with inadequate disease control on conventional therapy; the safety of the two treatment approaches was comparable.

Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis.

BACKGROUND: Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. AIM: To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. METHODS: We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. RESULTS: Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. CONCLUSION: This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis.

Magnetic resonance enterography is feasible and reliable in multicenter clinical trials in patients with Crohn's disease, and may help select subjects with active inflammation.

BACKGROUND: Reliable tools for patient selection are critical for clinical drug trials. AIM: To evaluate a consensus-based, standardised magnetic resonance enterography (MRE) protocol for selecting patients for inclusion in Crohn's disease (CD) multicenter clinical trials. METHODS: This study recruited 20 patients [Crohn's Disease Activity Index (CDAI) scores: <150 (n = 8); 150-220 (n = 4); 220-450 (n = 8)], to undergo ileocolonoscopy and two MREs (with and without colonic contrast) within a 14-day period. Procedures were scored centrally using, Magnetic Resonance Index of Activity (MaRIA), and both Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simplified Endoscopic Score (SES-CD). RESULTS: 37 MREs were acquired. Both MREs were evaluable in 16 patients for calculation of test-retest and inter-reader reliability scores. The MaRIA scores for the terminal ileum had excellent test-retest and inter-reader reliability, with correlations >0.9. The proximal ileum showed strong within-reader agreement (0.90-0.96), and fair between-reader agreement (0.59-0.72). MRE procedures were tolerable. MaRIA scores correlated with CDEIS and SES-CD (0.63 and 0.71), but not with CDAI (0.34). MRE identified 3 patients with intra-abdominal complications, who would otherwise have been included in clinical trials. Furthermore, both MRE and ileocolonoscopy identified active bowel wall inflammation in 2 patients with CDAI <150, and none in 1 patient with CDAI > 220. Data quality was good/excellent in 85% of scans, and fair or better in 96%. CONCLUSIONS: Magnetic resonance enterography of high-quality and reproducibility was feasible in a global multi- centre setting, with evidence for improved selectivity over CDAI and ileocolonoscopy in identifying appropriate CD patients for inclusion in therapeutic intervention trials.

IOIBD technical review on endoscopic indices for Crohn's disease clinical trials.

BACKGROUND: Crohn's disease (CD) is a chronic disabling and progressive IBD. Only strategies looking beyond symptoms and based on tight monitoring of objective signs of inflammation such as mucosal lesions may have the potential for disease modification. Endoscopic evaluation is currently the gold standard to assess mucosal lesions and has become a major therapeutic endpoint in clinical trials. Several endoscopic indices have been proposed to evaluate disease activity; unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response and endoscopic remission in CD. METHODS: In these recommendations from the International Organization for the Study of Inflammatory Bowel Disease, we first reviewed all technical aspects of available endoscopic scoring systems in the literature. Second, in order to achieve consensus on endoscopic definitions of remission and response in trials, a two-round vote based on a Delphi method was performed among 14 specialists in the field of IBDs. RESULTS: At the end of the voting process, the investigators ranked first a >50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) or Crohn's Disease Endoscopic Index of Severity for the definition of endoscopic response, and an SES-CD 0-2 for the definition of endoscopic remission in CD. All experts agreed on a Rutgeerts' score i0-i1 for the definition of endoscopic remission after surgery.