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Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: Background: Aminosalicylates are the most frequently prescribed drugs for patients with Crohn's disease (CD), yet evidence to support their efficacy as induction or maintenance therapy is controversial. Aims: To quantify aminosalicylate use in CD clinical trials, identify factors associated with use and estimate direct annual treatment costs of therapy. Methods: MEDLINE, Embase and CENTRAL were searched to April 2017 for placebo‐controlled trials in adults with CD treated with corticosteroids, immunosuppressants or biologics. The proportion of patients co‐prescribed aminosalicylates in placebo arms was pooled using a random‐effects model. Meta‐regression was used to identify factors associated with aminosalicylate use. Annual treatment costs were estimated using the 2016 Ontario Drug Benefit Program. Results: Forty‐two induction and 10 maintenance trials were included. The pooled proportion of patients co‐prescribed aminosalicylates was 44% [95% CI: 39%‐49%] in induction trials and 49% [95% CI: 35%‐64%] in maintenance trials. There was substantial to considerable heterogeneity (I2 = 86.0%, 91.8% for induction and maintenance trials, respectively). In multivariable meta‐regression, aminosalicylate use has decreased over time in induction trials (OR 0.50 [95% CI: 0.34–0.74] per 10‐year increment). While a decline has been seen over time, 35% of CD patients were still using aminosalicylates in contemporary trials from the last 5 years. The estimated annual cost for the lowest price mesalazine (mesalamine) formulation is approximately $32 million for the Canadian CD population. Conclusions: Over one‐third of CD patients entering clinical trials are still co‐prescribed aminosalicylates. A definitive trial is needed to inform the conventional practice of using aminosalicylates as CD maintenance therapy. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Health-related quality of life ( HRQL) is often diminished in patients with ulcerative colitis. Aim To evaluate the effects of vedolizumab on HRQL in patients with ulcerative colitis. Methods Using maintenance phase data from the GEMINI 1 study, an analysis of covariance model was used to calculate mean differences between the vedolizumab and placebo groups in changes from baseline to week 52 for 3 HRQL instruments: The Inflammatory Bowel Disease Questionnaire ( IBDQ), 36-Item Short Form Health Survey ( SF-36), and EQ-5D. Proportions of patients meeting minimal clinically important difference ( MCID) thresholds for changes on these instruments were compared between treatment groups for the overall population and for clinically important subgroups. Concordance between clinical remission and remission defined using IBDQ scores was examined. Results Compared with placebo-treated patients, vedolizumab-treated patients had greater improvements (152-201%) in IBDQ, EQ-5D visual analogue scale ( VAS), and EQ-5D utility scores. Greater proportions (6.9-19.9%) of vedolizumab-treated patients than placebo-treated patients met MCID thresholds for all the instruments. Vedolizumab-treated patients with lower baseline disease activity and those without prior tumour necrosis factor ( TNF) antagonist failure had greater HRQL improvements. Among 127 patients with clinical remission based on complete Mayo Clinic scores, >80% also had IBDQ remission; >70% of the 150 patients with IBDQ remission demonstrated clinical remission. Conclusions Vedolizumab therapy was associated with significant improvements in HRQL measures compared with placebo. Benefits were greater in patients with lower disease activity and no prior TNF antagonist failure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Many patients with active Crohn's disease do not adequately respond to therapies, highlighting the need for new treatments. Aims To conduct a randomised, double-blind, placebo-controlled phase 3 study to assess the efficacy and safety of vercirnon, an oral inhibitor of CC chemokine receptor-9, for the treatment of patients with moderately-to-severely active Crohn's disease. Methods Patients with a Crohn's Disease Activity Index ( CDAI) of 220-450, plus evidence of active disease (endoscopically confirmed or elevation of both C-reactive protein and faecal calprotectin), who had failed corticosteroid or immunosuppressant therapy were enrolled. Patients were equally randomised to receive placebo, vercirnon 500 mg once daily or vercirnon 500 mg twice daily. The primary endpoint was clinical response, defined as a 100-point decrease in CDAI from baseline to week 12. Results Six hundred and eight patients were randomised. Patient characteristics and baseline demographics were similar among the groups. The proportions of patients achieving a clinical response were 25.1%, 27.6% and 27.2% for placebo, once daily and twice daily respectively; treatment differences were not significant (2.5%; 95% confidence interval, CI −6.1% to 11.0%, P = 0.546 for once daily vs. placebo, and 2.1%; 95% CI −6.5% to 10.7%, P = 0.648 for twice daily vs. placebo). Adverse events were reported in 69.8%, 73.3% and 78.1% with serious adverse events in 8.9%, 5.9%, and 6.0% of patients in the placebo, once-daily and twice-daily groups, respectively. Conclusions We did not demonstrate efficacy of vercirnon as an induction therapy in patients with moderately-to-severely active Crohn's disease; its effect in maintenance therapy was not addressed. [ABSTRACT FROM AUTHOR]

Background Patient-reported outcomes ( PROs) have an increasingly important role in the evaluation of new therapies for inflammatory bowel disease. The US Food and Drug Administration has issued formal guidance to describe the role of PRO instruments in evaluation of claims for product labelling. However, no validated PRO exists for ulcerative colitis. Aim To investigate whether the PROs from the Mayo Clinic Score ( MCS) for UC can be modified, to develop an interim PRO for use in clinical trials, alone or in combination with endoscopy. Methods Data from an induction trial of a mesalazine (mesalamine) formulation were used to compare effect sizes between mesalazine and placebo for PRO items (stool frequency and rectal bleeding) alone and in combination with endoscopy. The operating properties of the PRO were validated using data from a phase 2 trial of MLN02, a humanised antibody to the α4 β7 integrin in patients with UC. Results A two-item PRO ( PRO2) consisting of rectal bleeding = 0 and stool frequency ≤1 or ≤2, combined with an endoscopy subscore ≤1 yielded statistically significant differences between active drug and placebo. This combination yielded the most similar effect sizes and placebo rates for remission, compared to the primary trials. Use of PRO items alone yielded high placebo remission rates in both data sets, although rates were lower when the items were combined and remission defined as PRO2 = 0. Conclusion Patient-reported outcomes items derived from the Mayo Clinic Score combined with endoscopy as a co-primary endpoint may be an appropriate interim outcome measure for ulcerative colitis trials. [ABSTRACT FROM AUTHOR]

Background Anti-tumour necrosis factor (anti- TNF) monoclonal antibodies have shown efficacy in inflammatory bowel diseases ( IBD). As these therapies lose patent protection, biosimilar versions of the originator products are being developed, such as the infliximab biosimilar CT-P13; however, some uncertainty exists regarding their pharmacology in IBD. Aim To review the literature on anti- TNF biosimilars focusing on pharmacokinetics, pharmacodynamic properties and comparative effectiveness, related to their use in IBD. Methods A PubMed literature search was performed using the following terms individually or in combination: 'biosimilars,' ' CT-P13,' 'Crohn's disease,' 'inflammatory bowel disease,' 'ulcerative colitis,' 'anti- TNFα therapy,' 'infliximab,' 'adalimumab,' 'pharmacokinetics,' 'immunogenicity.' Results Bioequivalence of CT-P13 and infliximab was shown in ankylosing spondylitis ( AS) and therapeutic equivalence in rheumatoid arthritis ( RA). Preliminary results of CT-P13 in IBD come from small post-marketing registries and case series with a relatively short-term follow-up period and suggest comparable efficacy and safety to infliximab. Inter- and intra-individual differences in exposure and response are well known for the original molecules but dosing regimens and concomitant medications are different for RA compared to IBD, limiting the ability to translate some of the pharmacology data in RA to IBD. Uncertainty exists about cross-reactivity of anti-drug antibodies and whether similar exposure-response relationships will be observed for biosimilars and efficacy thresholds for therapeutic drug monitoring can be used interchangeably. Conclusions It is likely that biosimilars will be widely used for the treatment of IBD due to their cost savings and comparable efficacy. Nevertheless, robust post-marketing studies and pharmacovigilance are warranted in the coming years. [ABSTRACT FROM AUTHOR]

Background Tumour necrosis factor alpha ( TNFα)-antagonism effectively treats ulcerative colitis (UC). The golimumab clinical programme evaluated subcutaneous (SC) and intravenous (IV) induction, and SC maintenance regimens, in TNFα-antagonist-naïve patients with moderate-to-severe active UC despite conventional treatment. Aim To evaluate dose-response relationship, select IV golimumab induction doses for continued development, and evaluate the safety and efficacy of selected doses. Methods Adults with Mayo scores of 6-12 and endoscopic subscores ≥2 were enrolled into this multicentre, randomised, double-blind, placebo-controlled, integrated Phase 2/3 dose-finding/dose-confirming study. In Phase 2, 176 patients were randomised (1:1:1:1) to a single IV infusion of placebo, 1-, 2- or 4-mg/kg golimumab. While Phase 2 data were analysed to select doses for continued development, 71 additional patients were randomised. Phase 3 enrolment stopped after 44 additional patients were randomised (1:1:1) to placebo, 2- or 4-mg/kg golimumab. Due to insufficient power for the Phase 3 primary endpoint analysis (clinical response at week 6), efficacy analyses are considered exploratory and include all randomised patients. Results No dose-response was observed in Phase 2; however, higher serum golimumab exposure was associated with greater proportions of patients achieving more favourable clinical outcomes, clinical response and greater improvement in Mayo scores compared with placebo-treated patients and those with lower serum concentrations. Among all randomised patients, numerically greater proportions were in clinical response at week 6 in the 2- and 4-mg/kg golimumab groups compared with placebo [44.0% (33/75) and 41.6% (32/77) vs. 30.1% (22/73)]. Conclusions Efficacy with single-dose golimumab IV induction was lower than expected and less than observed in the SC induction study. No new safety findings were observed. ClinicalTrials.gov Number, NCT00488774. [ABSTRACT FROM AUTHOR]

Background Vedolizumab, an anti-α4β7 integrin monoclonal antibody ( mAb), is indicated for treating patients with moderately to severely active ulcerative colitis ( UC) and Crohn's disease ( CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing. Aims To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic-pharmacodynamic relationship using population modelling. Methods Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/ CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data. Results Vedolizumab pharmacokinetics was described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half-life of vedolizumab was 25.5 days; linear clearance ( CLL) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution ( Vc) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (% CV) were 35% for CLL and 19% for Vc; residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CLL. Conclusions Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 ( GEMINI 1); NCT00783692 ( GEMINI 2); NCT01224171 ( GEMINI 3). [ABSTRACT FROM AUTHOR]

Background The Crohn's Disease Activity Index ( CDAI) is a measure of disease activity based on symptoms, signs and a laboratory test. The US Food and Drug Administration has indicated that patient reported outcomes ( PROs) should be the primary outcome in randomised controlled trials for Crohn's disease ( CD). Aim As no validated PRO exists for CD, to investigate whether CDAI diary card items could be modified for this purpose. Methods Data from a trial of rifaximin-extended intestinal release were used to identify cut-points for stool frequency, pain and general well-being using receiver operating characteristic curves with CDAI <150 as criterion. The operating properties of 2- and 3-item PRO were evaluated using data from a trial of methotrexate in CD. Regression analysis determined PRO2 and PRO3 scores that correspond to CDAI-defined thresholds of 150, 220 and 450 and changes of 50, 70 and 100 points. Results Optimum cut-points for CDAI remission were mean daily stool frequency ≤1.5, abdominal pain ≤1, and general well-being score of ≤1 (areas under the ROC curve 0.79, 0.91 and 0.89, respectively). The effect estimates were similar using 2- and 3-item PROs or CDAI. PRO2 and PRO3 values corresponding to CDAI scores of 150, 220 and 450 points were 8, 14, 34 and 13, 22, 53. The corresponding values for CDAI changes of 50, 70 and 100, were 2, 5, 8 and 5, 9, 14. Responsiveness to change was similar for both PROs. Conclusion Patient reported outcomes derived from CDAI diary items may be appropriate for use in clinical trials for CD. [ABSTRACT FROM AUTHOR]

Background Patients with Crohn's disease ( CD) may experience disease relapse on maintenance infliximab. Anti-drug antibodies likely contribute to loss of response, and serum infliximab levels likely correlate with efficacy. Aim To prospectively evaluate the relationship between trough serum infliximab concentration and disease activity. Methods Adult patients ( N = 327) with a diagnosis of CD who had received at least five consecutive infliximab infusions and who planned to receive at least two additional infusions were enrolled. The Crohn's Disease Activity Index ( CDAI), serum infliximab, C-reactive protein ( CRP) and antibodies-to-infliximab ( ATI) were assessed at baseline, week 4 and week 8. Receiver operating characteristic ( ROC) analysis examined the relationship between infliximab concentrations and disease activity. Results The mean CDAI score, which decreased 1.05 points between infusions, did not correlate with the mean change in trough infliximab concentration (+0.39 μg/mL; r = 0.099, P = 0.083), but was associated with the mean change in CRP concentration ( r = 0.19, P < 0.001). Trough infliximab concentrations below 2.8-4.6 μg/mL best predicted a ≥ 70 point increase in the CDAI between infusions, and those below 2.7-2.8 μg/mL best predicted CRP >5 mg/mL at the second infusion. ATI at either visit decreased the proportion of patients with therapeutic infliximab trough levels compared with patients who were ATI negative (17.5% vs. 77.3% at visit 1 and 13.8% vs. 75.6% at visit 3; P < 0.001 for both comparisons). Conclusions This prospective study confirms the relationship between trough infliximab concentrations, inflammation and antibodies-to-infliximab. Infliximab trough concentrations below 3 μg/mL may increase the likelihood of symptoms and inflammation (ClinicalTrials.gov identifier: NCT00676988). [ABSTRACT FROM AUTHOR]

Background Tumour necrosis factor ( TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases ( IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies ( ADAs) may decrease their efficacy. Aim The evidence supporting the use of therapeutic drug monitoring ( TDM) based clinical algorithms for infliximab ( IFX) and their role in clinical practice will be discussed. Methods The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. Results Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. Conclusions Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials. [ABSTRACT FROM AUTHOR]

Crohn's disease and ulcerative colitis are chronic inflammatory disorders resulting from immune dysregulation. Patients who fail conventional medical therapy require biological treatment with monoclonal antibodies (mAbs). Although mAbs are highly effective for induction and maintenance of clinical remission, not all patients respond, and a high proportion of patients lose response over time. One factor associated with loss of response is immunogenicity, whereby the production of antidrug antibodies accelerates mAb clearance. However, other factors related to patient and disease characteristics also influence the pharmacokinetics of mAbs. These factors include gender, body size, concomitant use of immunosuppressive agents, disease type, serum albumin concentration, and the degree of systemic inflammation. Because it is important to maintain clinically effective concentrations to provide optimal clinical response and drug exposure is affected by patient factors, a better understanding of the pharmacology of mAbs will ultimately result in better patient care. [ABSTRACT FROM AUTHOR]

Background Successful treatment of systemic inflammatory symptoms is essential for improving health-related quality of life in patients with active Crohn's disease. Patient-reported outcomes provide unique perspectives on the impact of chronic disease. It is unknown whether a combination of different instruments might improve sensitivity to clinically relevant changes in health status. Aim To develop a composite score based upon Crohn's Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ) items. Methods Patients from the PRECiSE 2 trial who responded at week 6 to certolizumab pegol (CZP) were randomised to receive treatment with CZP 400 mg or placebo for up to 26 weeks. IBDQ and CDAI scores were assessed at weeks 0, 6, 16 and 26. A 'daily practice' composite score (DP-6) containing two items from the CDAI and four items from IBDQ was constructed. Results Correlation coefficients between the CDAI score and IBDQ total score at baseline and at week 26 were -0.344 and -0.603, respectively (P < 0.05). All IBDQ items were improved following CZP treatment. The DP-6 had the highest responsiveness at assessing response to treatment, relative to CDAI total score, when compared with other scores. Conclusions The DP-6 composite score could be used to optimise the use of existing instruments by serving as an index of symptoms due to systemic inflammation. Additional studies are needed to determine if the DP-6 composite score differentiates the impact of different treatments on patient-reported outcomes, and to determine if the use of the DP-6 improves the care of patients in clinical practice. [ABSTRACT FROM AUTHOR]

Background Crohn's disease (CD) is associated with impaired health-related quality of life (HRQoL). Certolizumab pegol, administered either every 2 weeks (q2w) or q4w, maintains efficacy in patients previously failing on the anti-TNF agent infliximab (WELCOME study). Aim To investigate the impact of certolizumab pegol administered q2w and q4w on work productivity and HRQoL in the WELCOME study. Methods Patients with loss of response to infliximab received open-label certolizumab pegol induction and were randomised to receive double-blind maintenance treatment with certolizumab pegol 400 mg either q4w or q2w through week 24, with a final evaluation at week 26. Work productivity and HRQoL were assessed using the Work Productivity and Activity Impairment:CD questionnaire and Inflammatory Bowel Disease Questionnaire respectively. Results Baseline HRQoL burden was representative of moderately to severely active CD. HRQoL, daily activity and work productivity improved in both treatment groups as early as week 6 and were maintained through week 26. Treatment benefits to HRQoL, daily activity and work productivity were similar between the certolizumab pegol q2w vs. q4w groups. Conclusions Certolizumab pegol therapy results in meaningful improvements in work productivity, daily activities and HRQoL in patients with active CD who previously responded to but either lost response or could not tolerate infliximab (ClinicalTrials.gov number: NCT00308581). [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 31, 1276–1285 Background The effect of certolizumab pegol on employment status and work productivity has not been previously assessed. Aim To assess the impact of treatment with certolizumab pegol, the only PEGylated, Fab′ TNF antagonist, on work productivity in patients with active Crohn’s disease (CD) from the PRECiSE 2 study. Methods Patients ( n = 668) with active disease [CD activity index (CDAI) score of 220–450] were treated with open-label subcutaneous certolizumab pegol 400 mg (week 0, 2, 4). Responders ( n = 425) (≥100-point decrease in CDAI from baseline) were randomized to receive certolizumab pegol 400 mg or placebo every 4 weeks until week 24, with final evaluation at week 26. Patients completed the Work Productivity and Activity Impairment for CD questionnaire (WPAI:CD) and the Inflammatory Bowel Disease Questionnaire (IBDQ) at weeks 0, 6, 16 and 26 and at the withdrawal visit. Results Work productivity improved following induction with certolizumab pegol. Between week 6 and 26, certolizumab pegol-treated patients experienced significant improvement in work productivity compared with placebo recipients (11% and 10% overall improvement in work and activity impairment, respectively). During the maintenance phase, impairments in productivity and activities due to CD were significantly less in the certolizumab pegol group than in the placebo group. Conclusion Induction and maintenance therapy with certolizumab pegol significantly improved the work productivity of patients with active CD compared with those in the placebo group. [ABSTRACT FROM AUTHOR]

Background Crohn’s disease (CD) is a chronic inflammatory illness characterized by episodic abdominal pain, diarrhoea, fever, bleeding and obstruction. While the Crohn’s Disease Activity Index (CDAI) remains the most commonly accepted measure for assessing the disease status in clinical trials, patient-reported outcome (PRO) instruments are being utilized more frequently to provide information about health-related quality of life (HRQOL). To facilitate interpretation of results, it is common to identify a meaningful unit of PRO score change, such as a minimal clinically important difference (MCID). Aim To define and apply MCID estimates for the SF-36 and EuroQol-5D visual analogue scale (EQ-5D VAS) for use in CD treatment evaluation. Methods Data from two phase III randomized controlled trials of certolizumab pegol were utilized. MCID estimates were computed from one trial using anchor-based and distribution-based methods. These estimates were applied to data from the other trial. Results SF-36 PCS and MCS MCID estimates ranged from 1.6 to 7.0 and 2.3 to 8.7 respectively, depending on approach. EQ-5D VAS MCID estimates ranged from 4.2 to 14.8. Conclusions For the first time, the MCID values provided interpretation guidelines for PRO results in CD. This research demonstrates that patients treated with certolizumab pegol benefit from meaningful and sustained HRQOL improvements. [ABSTRACT FROM AUTHOR]

Background Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the intestine, which frequently require surgery for complications or failure of medical therapy. Aim To seek evidence and provide direction for clinicians on optimal strategies to enable steroid free remission in inflammatory bowel disease. Methods Scientific literature was reviewed using MEDLINE with a specific focus on medical therapies for inducing and maintaining remission of CD and UC. The results were discussed at a roundtable meeting to reach a consensus on key issues. Results Several therapies have demonstrated efficacy for the treatment of active, moderate-to-severe CD and UC. These include agents, which induce remission [corticosteroids, infliximab and adalimumab (CD only)] or maintain remission and spare corticosteroids [azathioprine, mercaptopurine, methotrexate (CD only), infliximab and adalimumab (CD only)]. Wide variability exists in the use of these agents. Conclusion Treatment strategy algorithms are developed for use of these therapies that maximize remission and minimize corticosteroid dependence in patients with moderate-to-severe CD and UC. [ABSTRACT FROM AUTHOR]

Background Patients with Crohn’s disease alternate between periods of active, symptomatic disease and periods of remission. The treatment goal for Crohn’s disease is to induce and then maintain remission of symptoms. Aim To review evidence from randomized, controlled, clinical trials on medical therapies for inducing and maintaining remission in patients with mild-to-moderate Crohn’s disease, and to suggest the best evidence-based approaches for induction and maintenance therapies. Methods PubMed search using the following terms: sulfasalazine or salicylazosulfapyridine or aminosalicylate or aminosalicylic acid or mesalamine or mesalazine or corticosteroid or prednisone or prednisolone or methylprednisolone or budesonide or antibiotic or metronidazole or ciprofloxacin or immunosuppressive or azathioprine or mercaptopurine or thiopurine or methotrexate and Crohn’s disease. Results Randomized, controlled trials demonstrated that sulfasalazine, budesonide, and conventional corticosteroids are effective for inducing remission of mild-to-moderate Crohn’s disease when administered for a period of 8–16 weeks. An ideal maintenance therapy does not currently exist. Conclusions Selection of maintenance therapy is based on a combination of evidence from controlled trials and patient features including disease severity and location, co-morbidities, previous response to treatment, and previous surgical resection. The options for maintenance therapy include therapy cessation and patient observation following successful induction, budesonide, or immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Background More than 50% of patients with Crohn's disease become either steroid resistant or dependent. Accordingly, development of new treatments for steroid-dependent Crohn's disease is a research priority. Aim To evaluate CDP571, a humanized antibody to tumour necrosis factor- α, for the treatment of steroid-dependent Crohn's disease. Methods Patients with steroid-dependent Crohn's disease ( n = 271) were enrolled in a 36-week, double-blind, placebo-controlled trial. Steroid dependence was defined as use of prednisolone or prednisone (15–40 mg/day) or budesonide (9 mg/day) for ≥8 weeks, a previous failed attempt to decrease or discontinue steroids within 8 weeks of screening, and a Crohn's Disease Activity Index score of ≤150 points. Patients were randomized to receive intravenous CDP571 10 mg/kg or placebo 8-weekly through to week 32. Steroids were then tapered using a defined schedule. The primary efficacy endpoint was the percentage of patients with steroid sparing, defined as discontinuation of steroid therapy without a disease flare (Crohn's Disease Activity Index score ≥220 points) at week 36. Results Steroid sparing occurred in 53 of 181 (29.3%) CDP571 patients and 33 of 90 (36.7%) placebo patients ( P = 0.24). Adverse events occurred at similar frequencies in both treatment groups. Conclusions CDP571 was ineffective for sparing steroids in patients with steroid-dependent Crohn's disease. CDP571 was well tolerated. [ABSTRACT FROM AUTHOR]

: To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-α, for the treatment of corticosteroid-dependent Crohn's disease.: Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15–40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score≥220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16.: Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo.: The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease. [ABSTRACT FROM AUTHOR]

Summary Previously, clinicians have had few choices in treating mild to moderate Crohn's disease. They currently treat these Crohn's disease patients with oral mesalamine and antibiotics. This treatment approach is based on the safety of these agents, and the perception that they are effective. This perception regarding efficacy may be influenced by publication bias. This review examines the efficacy and safety data of the conventional corticosteroids, mesalamine, sulfasalazine, budesonide and antibiotics for inducing the remission of mild to moderate Crohn's disease from randomized controlled trials, and proposes an evidence-based treatment approach. Sulfasalazine has demonstrated modest efficacy when Crohn's disease is confined to the colon. Mesalamine has no clear benefit over placebo in treating active Crohn's disease. Conventional corticosteroids effectively induce remission but are associated with unwanted adverse effects. Budesonide has similar efficacy to conventional steroids with far fewer adverse effects. Antibiotics have not consistently demonstrated efficacy. We propose a new evidence-based approach which suggests inducing remission of mild to moderate Crohn's disease with budesonide 9 mg/day for patients with ileal and/or right colonic involvement; sulfasalazine for those with disease limited to the colon; and conventional steroids for high disease activity, those who failed budesonide and those with left-sided disease who are allergic or intolerant to sulfasalazine. [ABSTRACT FROM AUTHOR]

Summary Aim : To assess the effectiveness and safety of budesonide in comparison to corticosteroids, 5-aminosalicylic acid (5-ASA), or placebo for inducing remission of active Crohn's disease and for maintaining remission. Study selection criteria : Randomized controlled trials comparing budesonide to corticosteroids, 5-ASA products or placebo were included. Trials had to report on the effectiveness of treatment (defined as decreasing or maintaining Crohn's Disease Activity Index, CDAI, scores ≤ 150) or adverse events. Data analysis : After assessing the validity of study design and independent, duplicate data extraction from selected trials, summary relative risks (RR) were calculated for each outcome. A test of heterogeneity was also calculated for each outcome using a random effects model. Results : Budesonide was more likely to induce remission than placebo (RR=1.82, 95% CI: 1.15–2.88) or 5-ASA (RR=1.73, 95% CI: 1.26–2.39), although only one trial compared budesonide to 5-ASA products. Although budesonide induced remission less frequently than conventional corticosteroids (RR=0.87, 95% CI: 0.76–0.995), there was no significant difference between conventional corticosteroids and budesonide for inducing remission among patients with a low disease activity (initial CDAI=200–300). Budesonide was significantly less likely to cause corticosteroid-associated adverse events than conventional corticosteroids (RR=0.65, 95% CI: 0.53–0.80). No significant difference in total adverse events or corticosteroid-associated adverse events was demonstrated between budesonide and 5-ASA or placebo. Conclusion : Budesonide is significantly more effective than placebo or 5-ASA for inducing remission of active Crohn's disease. Although budesonide is 13% less effective for the induction of remission in active Crohn's disease than conventional corticosteroids, it is less likely to cause corticosteroid-related adverse effects. Budesonide is... [ABSTRACT FROM AUTHOR]

The authors respond to an editorial which highlighted challenges in the investigation of eosinophilic oesophagitis (EoE). They cite two treatment objectives for EoE patients, including a significant reduction in symptoms and prevention of remodeling and stricture formation. They also emphasize the need to further establish the clinical validity of the EoE histological scoring system (EoEHSS).

Linked Content This article is linked to Jairath et al and Bernstein papers. To view these articles visit https://doi.org/10.1111/apt.13973 and https://doi.org/10.1111/apt.14036. [ABSTRACT FROM AUTHOR]

A response from authors of the article "A prospective cohort study to determine the relationship between serum infliximab concentration and efficacy in patients with luminal Crohn's disease" in a previous issue is presented.

Background: Medical therapy and/or endoscopic balloon dilation with intralesional therapies are options for the treatment of small bowel fibrostenotic Crohn's disease (CD)., Aim: To perform a systematic review summarising evidence for efficacy of systemic and endoscopic intralesional medical therapy in established small bowel strictures in adult CD patients., Methods: A systematic search of MEDLINE, EMBASE, CENTRAL and Scopus was conducted. Primary outcomes were rates of surgical resection and repeat endoscopic dilation. Pooled event rates from random effects models across studies with 95% confidence intervals were reported., Results: Ten studies describing systemic medical therapy and eight studies of intralesional injection were included. One randomised controlled trial each for systemic therapy and intrastricture injection were identified. Only observational studies were found for systemic biologic therapies, which exclusively included tumour necrosis factor (TNF) antagonists, while intralesional therapies all involved corticosteroids except for one study that evaluated infliximab. Pooled event rates for surgical resection after systemic and intralesional therapy were 28.3% (95% CI: 18.2%-41.3%) and 18.5% (95% CI: 8.3%-36.2%), respectively over a median follow-up of 23 months (range 5.5-105.8), and 21.8 months (range 5-47). Risk of repeat endoscopic balloon dilation in those with intralesional therapy was 58.3% (95% CI: 36.6%-77.3%) over a median follow-up of 21.8 months (range 5-47)., Conclusions: There are no favoured therapies for patients with stricturing small bowel CD. Data are lacking for ustekinumab and vedolizumab. No endoscopic intralesional medications provided a clear benefit for prevention of repeat EBD or surgery., (© 2020 John Wiley & Sons Ltd.)

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., (© 2017 John Wiley & Sons Ltd.)

Previously, clinicians have had few choices in treating mild to moderate Crohn's disease. They currently treat these Crohn's disease patients with oral mesalamine and antibiotics. This treatment approach is based on the safety of these agents, and the perception that they are effective. This perception regarding efficacy may be influenced by publication bias. This review examines the efficacy and safety data of the conventional corticosteroids, mesalamine, sulfasalazine, budesonide and antibiotics for inducing the remission of mild to moderate Crohn's disease from randomized controlled trials, and proposes an evidence-based treatment approach. Sulfasalazine has demonstrated modest efficacy when Crohn's disease is confined to the colon. Mesalamine has no clear benefit over placebo in treating active Crohn's disease. Conventional corticosteroids effectively induce remission but are associated with unwanted adverse effects. Budesonide has similar efficacy to conventional steroids with far fewer adverse effects. Antibiotics have not consistently demonstrated efficacy. We propose a new evidence-based approach which suggests inducing remission of mild to moderate Crohn's disease with budesonide 9 mg/day for patients with ileal and/or right colonic involvement; sulfasalazine for those with disease limited to the colon; and conventional steroids for high disease activity, those who failed budesonide and those with left-sided disease who are allergic or intolerant to sulfasalazine.

Aim: To assess the effectiveness and safety of budesonide in comparison to corticosteroids, 5-aminosalicylic acid (5-ASA), or placebo for inducing remission of active Crohn's disease and for maintaining remission., Study Selection Criteria: Randomized controlled trials comparing budesonide to corticosteroids, 5-ASA products or placebo were included. Trials had to report on the effectiveness of treatment (defined as decreasing or maintaining Crohn's Disease Activity Index, CDAI, scores < or = 150) or adverse events., Data Analysis: After assessing the validity of study design and independent, duplicate data extraction from selected trials, summary relative risks (RR) were calculated for each outcome. A test of heterogeneity was also calculated for each outcome using a random effects model., Results: Budesonide was more likely to induce remission than placebo (RR=1.82, 95% CI: 1.15-2.88) or 5-ASA (RR=1.73, 95% CI: 1.26-2.39), although only one trial compared budesonide to 5-ASA products. Although budesonide induced remission less frequently than conventional corticosteroids (RR=0.87, 95% CI: 0.76-0.995), there was no significant difference between conventional corticosteroids and budesonide for inducing remission among patients with a low disease activity (initial CDAI=200-300). Budesonide was significantly less likely to cause corticosteroid-associated adverse events than conventional corticosteroids (RR=0.65, 95% CI: 0.53-0.80). No significant difference in total adverse events or corticosteroid-associated adverse events was demonstrated between budesonide and 5-ASA or placebo., Conclusion: Budesonide is significantly more effective than placebo or 5-ASA for inducing remission of active Crohn's disease. Although budesonide is 13% less effective for the induction of remission in active Crohn's disease than conventional corticosteroids, it is less likely to cause corticosteroid-related adverse effects. Budesonide is ineffective in maintaining remission.

Recent clinical trials in patients with community-acquired pneumonia (CAP) demonstrated that switching from intravenous to oral antibiotic therapy is safe once clinical improvement is evident, thereby facilitating early hospital discharge. This study evaluated the use of a critical pathway to improve the efficiency of treating CAP in 1743 patients at 19 teaching and community hospitals in Canada. Hospitals were randomized to continue conventional management of CAP (10 hospitals) or implement a critical pathway (9 hospitals). The main clinical outcome measure was patients' scores (assessed 6 wks after hospital presentation) on the Short-Form 36 Physical Component Summary, a quality-of-life questionnaire. Secondary clinical outcome measures included occurrence of complications, readmission rates, and mortality. The primary economic outcome measure was resource utilization, measured by the number of bed days/patient managed (BDPM). Clinical outcomes were good in both groups, with no significant differences between the two management strategies. However, use of the clinical pathway was associated with a 1.7-day reduction in BDPM and fewer admissions of low-risk patients.

The advent of highly effective yet costly new treatments for Crohn's disease will force clinicians, patients, and society to make important choices regarding the allocation of resources. Pharmacoeconomic analyses can be useful in deciding whether new technologies are of good value in comparison to established treatment regimens. In Crohn's disease conventional cost-effectiveness analyses are of limited use because surgery, death, and disease-related complications occur relatively infrequently. Alternatively, cost-utility models relate the incremental cost of new treatments to improvements in health-related quality of life. These analyses require the collection of valid cost and utility inputs that have only recently become available. Ultimately, cost-utility models should allow decision makers to make sensible choices for patients and society. This article describes the techniques of pharmacoeconomic analysis and reviews existing data on the measurement of costs and quality-of-life outcomes in Crohn's disease.