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Background: STARDUST, a phase 3b randomised trial, compared ustekinumab therapeutic strategies in patients with Crohn's disease (CD) using early endoscopic assessment and treat-to-target (T2T) versus standard of care (SoC)., Aim: To assess the efficacy of ustekinumab extended treatment in a long-term extension (LTE) of up to 104 weeks with dosing adapted according to clinical, biomarker and endoscopy outcomes., Methods: Adults with moderately-to-severely active CD received intravenous ustekinumab approximating 6 mg/kg at Week 0 and subcutaneous ustekinumab 90 mg at Week 8. At Week 16, 440 ≥70-point responders were randomised to T2T or SoC and 323 entered the LTE. At Week 48, a unified, protocol-defined ustekinumab dose frequency escalation/de-escalation was applied based on achieving endoscopic remission and corticosteroid-free clinical remission. Achieving corticosteroid-free clinical remission and biomarker remission at consecutive visits determined ustekinumab dosing frequency. Dichotomous variables were analysed using non-responder imputation., Results: Among patients who entered the LTE, 7.7%, 48.6% and 43.7% received doses every 4, 8 and 12 weeks, respectively. Ustekinumab dose frequency was escalated in 23.5% and de-escalated in 19.7%. Endoscopic response and remission rates were 28.9% and 10.73% (all randomised) and 39.3% and 14.6% (patients entering the LTE), respectively, at Week 104. Clinical remission a rates at week 104 were 50.2% (all randomised) and 68.4% (patients entering the LTE). There were no new safety signals., Conclusion: STARDUST LTE is the first interventional ustekinumab efficacy study to show a favourable benefit-risk profile with preservation of clinical and endoscopic outcomes through Week 104 using flexible, algorithm-driven dose adjustment including de-escalation., (© 2023 Janssen Pharmaceuticals and The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background/aims: This analysis estimated the number of inflammatory bowel disease (IBD) patients presenting criteria of eligibility for biological therapies in an Italian real-world setting., Methods: An observational analysis was performed on administrative databases of a sample of Local Health Units, covering 11.3% of the national population. Adult IBD patients (CD or UC) from 2010 to the end of data availability were included. Eligibility criteria for biologics were the following: Criterion A, steroid-refractory active disease; Criterion B, steroid-dependent patients; Criterion C, intolerance or contraindication to conventional therapies; Criterion D, severe relapsing disease; Criterion E (CD only), highly active CD disease and poor prognosis., Results: Of 26,781 IBD patient identified, 18,264 (68.2%) were treated: 3,125 (11.7%) with biologics and 15,139 (56.5%) non-biotreated. Among non-biotreated, 7,651 (28.6%) met at least one eligibility criterion for biologics, with criterion B (steroid-dependence) and criterion D (relapse) as the most represented (58-27% and 56-76%, respectively). Data reportioned to the Italian population estimated 67,635 patients as potentially eligible for biologics., Conclusions: This real-world analysis showed a trend towards undertreatment with biologics in IBD patients with 28.6% being potentially eligible, suggesting that an unmet medical need still exists among the Italian general clinical practice for IBD management., Competing Interests: Declaration of Competing Interest Flavio Caprioli served as consultant to: Abbvie, MSD, Takeda, Janssen, Roche, Celgene, Bristol-Meyers Squibb, Galapagos, Gllead, Pfizer, Mundipharma, Galapagos, Biogen, Ferring. He received lecture fees from Abbvie, Ferring, Takeda, Allergy Therapeutics, Janssen, Pfizer, Biogen, and unrestricted research grants from Giuliani, Sofar, MSD, Takeda, Abbvie, Celltrion, Pfizer. All the other coauthors have no competing interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

Background and Aims: Endoscopic assessment of disease activity is integral for evaluating treatment response in patients with Crohn's disease (CD). We aimed to define appropriate items for evaluating endoscopic activity and conventions for consistent endoscopic scoring rules in CD., Methods: A 2-round modified RAND/University of California at Los Angeles Appropriateness Method study was conducted. A panel of 15 gastroenterologists used a 9-point Likert scale to rate the appropriateness of statements pertaining to the Simple Endoscopic Score for CD, Crohn's Disease Endoscopic Index of Severity, and additional items relevant to endoscopy scoring in CD. Each statement was voted as appropriate, uncertain, or inappropriate based on the median panel rating and presence of disagreement., Results: Panelists voted that it is appropriate for all ulcers to contribute to endoscopic scoring in CD, including aphthous ulcers, ulcerations at a surgical anastomosis, and anal canal ulcers (scored in the rectum). Endoscopic healing should reflect an absence of ulcers. Narrowing should be defined as a clear decrease in luminal diameter; stenosis should be defined by an impassable narrowing, and if occurring at the junction of 2 segments, scored in the distal segment. Scarring and inflammatory polyps were considered inappropriate for including in the affected area score. The optimal method for defining ulcer depth remains uncertain., Conclusions: We outlined scoring conventions for the Simple Endoscopic Score for CD and Crohn's Disease Endoscopic Index of Severity, noting that both scores have limitations. Therefore, we identified priorities for future research and steps for developing and validating a more representative endoscopic index in CD., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background/aims: This real-world analysis evaluated the persistence and direct healthcare costs of Crohn's Disease (CD) patients treated with biologics in Italy., Methods: A retrospective analysis on administrative databases of Italian healthcare entities, covering 10.4 million residents, was performed. Adult CD patients under biologics between 2015 and 2020 were included and attributed to first/second treatment line based on absence/presence of biologic prescriptions 5-years before index-date (first biologic prescription)., Results: Of 16,374 CD patients identified, 1,398 (8.5%) were biologic-treated: 1,256 (89.8%) in first line and 135 (9.7%) in second line. Kaplan-Meier curves estimated a higher persistence for ustekinumab-treated patients followed by vedolizumab, infliximab and adalimumab, in both lines. Considering baseline variables and adalimumab as reference, infliximab in first line (HR: 0.537) and ustekinumab in first (HR: 0.057) and second line (HR: 0.213) were associated with significantly reduced risk of drug-discontinuation. First line total/average healthcare direct-costs were €13,637, €11,201, €17,104 and €18,340 in patients persistent on adalimumab, infliximab, ustekinumab and vedolizumab, respectively., Conclusions: This real-world analysis showed differences in persistence over 12-months between biologic treatments, being higher in ustekinumab-treated group, followed by vedolizumab, infliximab and adalimumab. Patients' management was associated with comparable direct healthcare costs among treatment lines, mainly driven by drug-related expenses., Competing Interests: Conflict of Interest Janssen-Cilag SpA purchased the study report that is the basis for this manuscript. This manuscript was developed with Janssen-Cilag SpA and CliCon S.r.l. Società Benefit. The views expressed here are those of the authors and not necessarily those of the supporters. The agreement signed by CliCon S.r.l. and Janssen-Cilag SpA does not create any entity, joint venture or any similar relationship between parties. CliCon S.r.l. is an independent company. Neither CliCon S.r.l. nor any of their representatives are employees of Janssen-Cilag SpA for any purpose. Andrea Franchi, Ottavio Secchi and Andrea Serra are employees of Janssen-Cilag SpA. Marco Daperno served as member of boards, lecturer and/or received grants for participation to congresses from Abbvie, Takeda, Jannsen, Pfizer, Celltrion, Galapagos, SOFAR, Chiesi, Zambon, Ferring; he acts as consultant for Bioclinica-Clario. Edoardo Vincenzo Savarino has served as speaker for Abbvie, AGPharma, Alfasigma, Dr Falk, EG Stada Group, Fresenius Kabi, Grifols, Janssen, Innovamedica, Malesci, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Unifarco; has served as consultant for Alfasigma, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fresenius Kabi, Janssen, Merck & Co, Reckitt Benckiser, Regeneron, Sanofi, Shire, SILA, Sofar, Synformulas GmbH, Takeda, Unifarco; he received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco. Franco Scaldaferri received fees for consultancy or other activities form MSD, Janseen, Takeda, Sandoz, Ferring, Pfizer. or other activities. Alessandro Armuzzi has received consulting fees from: AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda; speaker's fees from: AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Tigenix; research support from: MSD, Takeda, Pfizer, Biogen. All the other authors have no competing interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A cure for Crohn's disease (CD), a chronic inflammatory disease of the gastrointestinal tract of unknown etiology, is not available, so patients require lifelong management to keep inflammation under control. The therapeutic armamentarium has expanded with approval of several biological drugs, including infliximab, adalimumab, vedolizumab and ustekinumab - monoclonal antibodies that target different inflammatory pathways - and darvadstrocel, a suspension of expanded human allogeneic, adipose-derived, mesenchymal stromal cells for the treatment of refractory complex perianal fistula. Notwithstanding existing practice guidelines on medical therapy for CD, the Italian Group for the Study of Inflammatory Bowel Disease felt the need to issue new guidelines focused on the use of biologics for managing the intestinal manifestations of CD and based on the GRADE methodology. This document presents recommendations regarding six clinical settings, from the induction to the maintenance of clinical remission, and from optimization and de-escalation of treatments to dealing with perianal CD and post-operative recurrence. The 19 evidence-based statements are supported by information on the quality of the evidence, agreement rate among panel members, and panel comments mainly based on evidence from real world studies., Competing Interests: Declaration of Competing Interest FSM served as an advisory board member and/or received lecture grants from AbbVie, Biogen, Galapagos, Janssen, MSD, Pfizer, Samsung Bioepis, and Takeda Pharmaceuticals. CP has received consultancy fees and/or educational grants from Abbvie, MSD, Takeda, Pfizer, Janssen-Cilag, Sandoz, Chiesi, Sofar, Ferring and Zambon. SF: advisory board for Janssen Cilag; consultancy fees and/or educational grants from Takeda, SoFar, Abbvie, Zambon. AO served as an advisory board member for AbbVie, Galapagos, MSD, Janssen, Pfizer, Takeda Pharmaceuticals, and received lecture grants from AbbVie, MSD, Sofar, Chiesi, Janssen, Pfizer, and Takeda Pharmaceuticals. DP received consultancy fees from Takeda, Jannsen-Cilag, Pfizer, and MSD. GF served as a consultant and advisory board member for Takeda, Abbvie, Janssen, Pfizer, Celltrion, Sandoz, AlfaSigma, Samsung Bioepis, Amgen, Roche, Ferring, Mylan, Galapagos. MCF received consultancy fees from Roche, Takeda, Jannsen-Cilag, Pfizer, Sandoz, Biogen, Galapagos and research economic support from Abbvie. FC served as consultant to Abbvie, MSD, Takeda, Janssen, Roche, Celgene, Bristol-Meyers Squipp, Galapagos, Gllead, Pfizer, Mundipharma, Galapagos, Biogen, received lecture fees from Abbvie, Ferring, Takeda, Allergy Therapeutics, Janssen, Pfizer, Biogen, and unrestricted research grants from Giuliani, Sofar, MSD, Takeda, Abbvie. MD served as advisor or received consultancy fees from: Roche, Takeda, Janssen, Pfizer, Abbvie, Bioclinica. AA: consulting and/or advisory board fees from AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Protegonist-Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda; lecture and/or speaker bureau fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mitsubishi Tanabe, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Tigenix; research grants: MSD, Pfizer, Takeda, and Biogen. SB, CP, and DP have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Telemonitoring is increasingly used in the management of IBD patients. We investigated the agreement between patients and physicians on scores of disease activity and burden., Methods: Consecutive outpatients at one IBD clinic were recruited between February and December 2021. Enrolled patients completed a questionnaire for disease activity (Harvey-Bradshaw Index [HBI] for Crohn's disease or Simple Clinical Colitis Activity Index [SCCAI] for ulcerative colitis) and a test of disease burden (Pictorial Representation of Illness and Self Measure [PRISM]). They did the tests within 5 days of an outpatient visit, working independently on IBD Tool, a new web-based telemonitoring application. Concomitantly, the senior and junior physicians who examined them completed the same tests. The agreement was tested for every pair of scores., Results: Five hundred and sixty patients (289 Crohn's disease; 271 ulcerative colitis) completed disease questionnaires on IBD Tool (in total, 742 times). By Spearman's correlation, the agreement was substantial both for HBI (rho 0.685-0.837) and SCCAI (rho 0.694-0.888) for comparisons between patients, junior and senior physicians. The agreement was moderate-to-substantial for PRISM (rho 0.406-0.725) for the same comparisons. The correlation between disease activity (HBI/SCCAI) and PRISM scores was substantial for senior (rho 0.757-0.788) or junior (rho 0.746-0.753) physicians and moderate for patients (rho 0.458-0.486). The median PRISM score difference was 2.3-1.6 points lower between patients and senior-junior physicians., Conclusion: Agreement between IBD patients and physicians was substantial for disease activity and moderate for disease impact. The inclusion of disease burden scoring in telemonitoring platforms provides important information for the management of IBD patients.Study highlightsWhat IS known•Continuous response to treatments and patient-reported outcomes became an essential goal for IBD patient management.•The use of tele-monitoring and eHealth technologies allows for regular disease assessments and for managing more efficiently IBD patients; disease questionnaires and tests are key to support eHealth tools.What is new here•Agreement between IBD patients and physicians was substantial for disease activity and moderate for disease burden, while agreement among junior and senior physicians was substantial for both.•PRISM performs as well for ulcerative colitis as for Crohn's patients.•The inclusion of disease burden tests might add to eHealth platforms valuable information, complemental to disease activity questionnaires.

Background: Etrolizumab is a gut-targeted anti-β7 monoclonal antibody targeting α4β7 and αEβ7 integrins. We aimed to compare the safety and efficacy of two doses of etrolizumab with placebo in patients with Crohn's disease., Methods: BERGAMOT was a randomised, placebo-controlled, double-blind, phase 3 study done at 326 treatment centres worldwide. We included patients aged 18-80 years with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220-480, and a mean daily stool frequency score of ≥6 or a mean daily stool frequency score of >3, and a mean daily abdominal pain score of >1, as well as the presence of active inflammation on screening ileocolonoscopy) who had intolerance, inadequate response, or no response to one or more of corticosteroids, immunosuppressants, or anti-TNF therapy within the past 5 years. BERGAMOT consisted of three induction cohorts (a placebo-controlled, double-blind exploratory cohort [cohort 1]; an active treatment cohort not containing a placebo control [cohort 2]; and a placebo-controlled, double-blind pivotal cohort [cohort 3]) and one maintenance cohort. In induction cohort 3, during the 14-week induction, patients were randomly assigned (2:3:3) to receive matched placebo, 105 mg etrolizumab subcutaneously every 4 weeks (at weeks 0, 4, 8, and 12) or 210 mg etrolizumab subcutaneously (at weeks 0, 2, 4, 8, and 12), stratified by concomitant treatment with oral corticosteroids, concomitant treatment with immunosuppressants, baseline disease activity, and previous exposure to anti-TNF therapy. To preserve masking, all patients received two injections at weeks 0, 4, 8, and 12 and one injection at week 2. Week 14 etrolizumab responders from all cohorts were re-randomly assigned (1:1) to receive 105 mg etrolizumab (etrolizumab maintenance group) or placebo (placebo maintenance group) every 4 weeks for 52 weeks; patients in the induction placebo group underwent a sham re-randomisation to preserve masking. During maintenance, randomisation was stratified by CDAI remission status, concomitant treatment with oral corticosteroids, induction dose regimen, and previous exposure to anti-TNF therapy. All participants and study site personnel were masked to treatment assignment for both induction and maintenance. Co-primary induction endpoints at week 14 (placebo vs 210 mg etrolizumab) were clinical remission (mean stool frequency ≤3 and mean abdominal pain ≤1, with no worsening) and endoscopic improvement (≥50% reduction in Simple Endoscopic Score for Crohn's Disease [SES-CD]). Co-primary maintenance endpoints at week 66 (placebo vs etrolizumab) were clinical remission and endoscopic improvement. Efficacy was analysed using a modified intention-to-treat (mITT) population, defined as all randomised patients who received at least one dose of study drug (induction) and as all patients re-randomised into maintenance who received at least one dose of study drug in the maintenance phase (maintenance). Safety analyses included all patients who received at least one dose of study drug. Maintenance safety analyses include all adverse events occurring in both induction and maintenance. This trial is registered with ClinicalTrials.gov, NCT02394028, and is closed to recruitment., Findings: Between March 20, 2015, and Sept 7, 2021, 385 patients (209 [54%] male and 326 [85%] white) were randomly assigned in induction cohort 3 to receive placebo (n=97), 105 mg etrolizumab (n=143), or 210 mg etrolizumab (n=145). 487 patients had a CDAI-70 response in any of the induction cohorts and were enrolled into the maintenance cohort, of whom 434 had a response to etrolizumab and were randomly assigned to placebo (n=217) or 105 mg etrolizumab (n=217). At week 14, 48 (33%) of 145 patients in the 210 mg induction etrolizumab group versus 28 (29%) of 96 patients in the placebo induction group were in clinical remission (adjusted treatment difference 3·8% [95% CI -8·3 to 15·3]; p=0·52), and 40 (27%) versus 21 (22%) showed endoscopic improvement (5·8% [-5·4 to 17·1]; p=0·32). At week 66, a significantly higher proportion of patients receiving etrolizumab than those receiving placebo had clinical remission (76 [35%] of 217 vs 52 [24%] of 217; adjusted treatment difference 11·3% [95% CI 2·7-19·7]; p=0·0088) and endoscopic improvement (51 [24%] vs 26 [12%]; 11·5% [4·1-18·8]; p=0·0026). Similar proportions of patients reported one or more adverse events during induction (95 [66%] of 143 in the 105 mg etrolizumab group, 85 [59%] of 145 in the 210 mg etrolizumab group, and 51 [53%] of 96 in the placebo group) and maintenance (189 [87%] of 217 in the etrolizumab group and 190 [88%] of 217 in the placebo group). During induction, the most common treatment-related adverse events were injection site erythema (six [4%] of 143 in the 105 mg etrolizumab group, four [3%] of 145 in the 210 mg etrolizumab group, and none of 96 in the placebo group), and arthralgia (two [1%], one [1%], and four [4%]). In the maintenance cohort, the most common treatment-related adverse events were injection site erythema (six [3%] of 217 in the etrolizumab group vs 14 [6%] of 217 in the placebo: group), arthralgia (five [2%] vs eight [4%]), and headache (five [2%] vs seven [3%]). The most common serious adverse event was exacerbation of Crohn's disease (14 [6%] of 217 patients taking placebo and four [2%] of 217 patients taking 105 mg etrolizumab in the maintenance cohort)., Interpretation: A significantly higher proportion of patients with moderately to severely active Crohn's disease achieved clinical remission and endoscopic improvement with etrolizumab than placebo during maintenance, but not during induction., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests WJS has received grants from Alimentiv, Arena, Boehringer Ingelheim, Celgene, Gilead, GSK, Janssen, Lilly, Pfizer, Prometheus, Roche/Genentech, Series Therapeutics, Shire, Takeda, and Theravance; personal fees from Alfasigma, Alimentiv, Alivio, Allakos, Amgen, Applied Molecular Transport, Arena, AstraZeneca, Atlantic Pharmaceuticals, Bausch Health, BeiGene, Bellatrix, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene, Celltrion, Celularity, ClostraBio, Codexis, Cosmo Pharmaceuticals, Equillium, Escalier Biosciences, Forbion, Galapagos, Gilead, Glenmark, Gossamer Bio, GSK, Immunic, InDex Pharmaceuticals, Inotrem, Intact Therapeutics, iota Biosciences, Janssen, Kiniksa, Kyverna, Landos Biopharma, Lilly, Morphic Therapeutics, Novartis, Ono, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Pharm-Olam, Progenity, Prometheus, Protagonist Therapeutics, Provention Bio, PTM Therapeutics, Quell Therapeutics, Reistone Biopharma, Roche/Genentech, Series Therapeutics Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sterna Biologicals, Sublimity, Surrozen, Takeda, Theravance, Thetis, Tillotts Pharma, UCB, Vedanta Biosciences, Ventyx Biosciences, Vivelix, Vividion, Vivreon Gastrosciences, Xencor, and Zealand Pharma; and stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Progenity, Prometheus, Protagonist Therapeutics, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Gastrosciences. JP has received grants from MSD; consulting fees from AbbVie, Arena, Boehringer Ingelheim, Celgene, GSK, Janssen, MSD, Nestlé, Oppilan Pharma, Pfizer, Progenity, Roche/Genentech, Takeda, Theravance, and TiGenix; and other fees and support from AbbVie and Takeda. SD has received consulting fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Dr Falk Pharma, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Lilly, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor. ZS, AH, RJ-M, and CE are employees of Roche/Genentech and receive salary and stock options. MD has received speaker fees from AbbVie, Janssen, Pfizer, Roche, and Takeda; consulting fees from Bioclinica; and other fees and support from AbbVie, Chiesi, Ferring, Janssen, Roche, SOFAR, and Takeda. JFV has received grants from AbbVie, Applied Molecular Transport, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Takeda. DL has received grants from AbbVie, Amgen, Fresenius Kabi, and Takeda; speaker fees from AbbVie, Ferring, Fresenius Kabi, Galapagos, Janssen, Pfizer, Takeda, and Tillotts Pharma; consulting fees from AbbVie, Bristol Myers Squibb, Fresenius Kabi, Galapagos, Janssen, MSD, Pfizer, Roche, Takeda, and Tillotts Pharma; and other fees and support from AbbVie, Janssen, Pfizer, and Sandoz. CB has received grants from Roche; speaker fees from AbbVie and Janssen; and other fees and support from AbbVie, Janssen, and Takeda. RA has received grants from AbbVie, Biogen, InDex Pharmaceuticals, Takeda, and Tillotts Pharma; speaker fees from AbbVie, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Ferring, Fresenius Kabi, Galapagos, InDex Pharmaceuticals, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Samsung Bioepis, Takeda, and Tillotts Pharma; consulting fees from AbbVie, Arena, Biogen, Boehringer Ingelheim, Galapagos, InDex Pharmaceuticals, Janssen-Cilag, Kliniksa Pharmaceuticals, Lilly, Samsung Bioepis, Stelic Institute, and Takeda; and other fees and support from AbbVie, Biogen, Dr Falk Pharma, and Janssen-Cilag. RP has received speaker fees and consulting fees from Roche/Genentech. SV has received grants from AbbVie, Galapagos, Janssen, Pfizer, and Takeda; speaker fees from AbbVie, Galapagos, Janssen, Pfizer, Roche/Genentech, and Takeda; and consulting fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Gilead, GSK, Hospira, IMIDomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Roche/Genentech, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma, and Zealand Pharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Assessment of mucosal healing is important for the management of patients with inflammatory bowel disease (IBD), but endoscopy can miss microscopic disease areas that may relapse. Histological assessment is informative, but no single scoring system is widely adopted. We previously proposed an eight-item histological scheme for the easy, fast reporting of disease activity in the intestine. The aim of the present study was to evaluate the performance of our Simplified Histologic Mucosal Healing Scheme (SHMHS)., Methods: Between April and May 2021 pathologists and gastroenterologists in Italy were invited to contribute to this multicenter study by providing data on single endoscopic-histological examinations for their IBD patients undergoing treatment. Disease activity was expressed using SHMHS (maximum score, 8) and either Simple Endoscopic Score for Crohn's Disease (categorized into grades 0-3) or Mayo Endoscopic Subscore (range 0-3)., Results: Thirty hospitals provided data on 597 patients (291 Crohn's disease; 306 ulcerative colitis). The mean SHMHS score was 2.96 (SD = 2.42) and 66.8% of cases had active disease (score ≥ 2). The mean endoscopic score was 1.23 (SD = 1.05), with 67.8% having active disease (score ≥ 1). Histologic and endoscopic scores correlated (Spearman's ρ = 0.76), and scores for individual SHMHS items associated directly with endoscopic scores (chi-square p < 0.001, all comparisons). Between IBD types, scores for SHMHS items reflected differences in presentation, with cryptitis more common and erosions/ulcerations less common in Crohn's disease, and the distal colon more affected in ulcerative colitis., Conclusions: SHMHS captures the main histological features of IBD. Routine adoption may simplify pathologist workload while ensuring accurate reporting for clinical decision making., (© 2022. The Author(s).)

Background and Aims: Current endoscopic scoring indices such as the Simple Endoscopic Score for Crohn's Disease [SES-CD] quantify the degree of mucosal inflammation in Crohn's disease [CD] but lack prognostic potential. The Modified Multiplier of the SES-CD [MM-SES-CD] quantifies the endoscopic burden of CD and can be accessed online [https://www.mcmasteribd.com/mm-ses-cd]. This analysis aims to establish MM-SES-CD thresholds that classify CD endoscopic burden into inactive/very mild, mild, moderate, and severe disease based on the probability of achieving endoscopic remission [ER] on active therapy at 1 year., Methods: This post-hoc analysis included pooled data from three CD clinical trials [n = 350 patients, baseline SES-CD ≥3 with ulceration]. Disease category severity was determined using the maximum Youden Index. Achievement of ER between severity categories was compared using chi square tests. Time to clinical remission [CR] was compared using Kaplan-Meier survival curves., Results: MM-SES-CD severity categories were established as very mild/remission [score <14], mild [≥14 to <31], moderate [≥31 to <45], and severe [≥45], which were predictive of 1-year ER [50%, 30.3%, 21.7%, 8.8%, respectively, p <0.001]. Lower MM-SES-CD scores had numerically higher rates of 1-year clinical remission [CR], and time to 1-year CR was superior to those with higher scores [p = 0.0492]. MM-SES-CD thresholds for achieving 1-year ileal ER among 75 patients with isolated ileal disease were established as mild [score <14], moderate [≥14 to <33], and severe [≥33], which were predictive of 1-year ER [66.7%, 33.3%, 13.3%, respectively, p = 0.027]., Conclusions: We have established numerical MM-SES-CD cut-offs that categorise endoscopic disease severity and have demonstrated that they are prognostic for 1-year ER and CR., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: The Simple Endoscopic Score for Crohn's disease (SES-CD) is the primary tool for measurement of mucosal inflammation in clinical trials but lacks prognostic potential. We set to develop and validate a modified multiplier of the SES-CD (MM-SES-CD), which takes into consideration each individual parameter's prognostic value for achieving endoscopic remission (ER) while on active therapy., Methods: In this posthoc analysis of three CD clinical trial programmes (n=350 patients, baseline SES-CD ≥ 3 with confirmed ulceration), data were pooled and randomly split into a 70% training and 30% testing cohort. The MM-SES-CD was designed using weights for individual parameters as determined by logistic regression modelling, with 1-year ER (SES-CD < 3) being the dependent variable. A cut point score for low and high probability of ER was determined by using the maximum Youden Index and validated in the testing cohort., Results: Baseline ulcer size, extent of ulceration and presence of non-passable strictures had the strongest association with 1-year ER as compared with affected surface area, with differential weighting of individual parameters across disease segments being observed during logistic regression. The MM-SES-CD was generated using this weighted regression model and demonstrated strong discrimination for ER in the training dataset (area under the receiver operator curve (AUC) 0.83, 95% CI 0.78 to 0.94) and in the testing dataset (AUC 0.82, 95% CI 0.77 to 0.92). In comparison to the MM-SES-CD scoring model, the original SES-CD score lacks accuracy (AUC 0.60, 95% CI 0.55 to 0.65) for predicting the achievement of ER., Conclusions: We developed and internally validated the MM-SES-CD as an endoscopic severity assessment tool to predict one-year ER in patients with CD on active therapy., Competing Interests: Competing interests: NN holds a McMaster University Department of Medicine Internal Career Award. NN has received honoraria from Janssen, Abbvie, Takeda, Pfizer, Merck, Sandoz, Novartis and Ferring. J-FC reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Genentech, Janssen Pharmaceuticals, Landos, Ipsen, Medimmune, Merck, Novartis, Pfizer, Shire, Takeda, Tigenix, Viela bio and hold stock options in Intestinal Biotech Development and Genfit. WJS is supported in part by the NIDDK-funded San Diego Digestive Diseases Research Center (P30 DK120515) grant. He has received: research grants from Abbvie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, Glaxo Smith Kline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, Theravance Biopharma; consulting fees from Abbvie, Abivax, Admirx, Alfasigma, Alimentiv (Robarts Clinical Trials, owned by Health Academic Research Trust (HART)), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Meyers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, Zealand Pharma; and stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences, Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences. Spouse: Iveric Bio—consultant, stock options; Progenity—stock; Oppilan Pharma—consultant, stock options; Prometheus Biosciences—employee, stock options; Ventyx Biosciences—stock options; Vimalan Biosciences—stock options. JKM has received honoraria from Janssen, AbbVie, Allergan, Bristol-Meyer-Squibb, Ferring, Janssen, Lilly, Lupin, Merck, Pfizer, Pharmascience, Roche, Shire, Takeda and Teva. MD served as a speaker, consultant and advisory board member for AbbVie, Takeda, Janssen, Norgine, Pfizer, MSD, Celltrion, Roche, Gilead, Bioclinica, Ferring, SOFAR, Chiesi, Zambo. WR has received support for the following: speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult, Consultant for Abbott Laboratories, Abbvie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernest & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia and 4SC, Advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia and 4SC. PD is supported by a Digestive Diseases Research Center grant NIH DK120515 and a Research Scholar Award from the American Gastroenterology Association. PD has received research support and consulting for Takeda, Abbvie, Janssen, Pfizer., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A treat-to-target strategy, in which strictly defined treatment targets facilitate decision making in clinical practice, is advocated as an optimised management approach for some chronic disorders. The aim of the STARDUST trial was to assess whether a treat-to-target strategy with early endoscopy, regular biomarker and clinical symptom monitoring, and dose intensification for persistent inflammatory activity, was more successful in achieving endoscopic improvement at week 48 than a clinically driven maintenance strategy in patients with moderate-to-severe active Crohn's disease receiving ustekinumab., Methods: This open-label, multicentre, randomised phase 3b trial included adults with active, moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450 and Simple Endoscopic Score in Crohn's Disease [SES-CD] ≥3) for whom conventional therapy or one biologic therapy, or both, had failed. Patients received intravenous ustekinumab approximating 6 mg/kg at baseline and subcutaneous ustekinumab 90 mg at week 8. At week 16, patients with a CDAI improvement of 70 or more points from baseline were randomly assigned (1:1) to receive standard-of-care or treat-to-target maintenance treatment through week 48. Randomisation was balanced by using randomly permuted blocks and was stratified by biologic history status and baseline SES-CD score. All patients who signed informed consent, who were not screening failures, and who received at least one dose of study treatment were included in week 16 analyses. All patients included in week 16 analyses and randomly assigned to one of the maintenance treatment regimens were included in the week 48 efficacy and safety analyses (ie, on an intention-to-treat basis). Patients assigned to the treat-to-target arm received ustekinumab every 12 weeks or every 8 weeks based on SES-CD improvement from baseline and could escalate to every 4 weeks through week 48 if prespecified targets were missed. Patients assigned to the standard-of-care arm received ustekinumab every 12 weeks or every 8 weeks; those receiving treatment every 12 weeks could escalate per European labelling. The primary efficacy endpoint was endoscopic response at week 48 (SES-CD score ≥50% decrease from baseline), analysed by non-responder imputation. This trial is registered at ClinicalTrials.gov, NCT03107793, and is active but not recruiting., Findings: 498 patients received standard induction treatment, of whom 440 were randomly assigned to the treat-to-target group (n=219) or the standard-of-care group (n=221). At week 48, there was no significant difference in endoscopic response (83 [38%] of 219 patients vs 66 [30%] of 221 patients; p=0·087), endoscopic remission (25 [11%] vs 32 [15%]; p=0·334), mucosal healing (31 [14%] vs 37 [17%]; p=0·449), and clinical remission (135 [62%] vs 154 [70%]; p=0·072) between the two groups; clinical response was significantly lower in the treat-to-target group than in the standard-of-care group (149 [68%] vs 172 [78%]; p=0·020). Other endoscopic, clinical, and biomarker outcomes were generally not significantly different between groups. The most commonly reported treatment-emergent adverse events were nasopharyngitis (29 [13%] of 219 patients in the treat-to-target group vs 29 [13%] of 221 patients in the standard-of-care group), abdominal pain (23 [11%] vs 19 [9%]), arthralgia (24 [11%] vs 19 [9%]), and headache (24 [11%] vs 21 [10%])., Interpretation: Timely escalation of ustekinumab therapy for patients with Crohn's disease, based on early endoscopic response, clinical symptoms, and biomarkers, did not result in significantly better endoscopic outcomes at week 48 than symptom-driven decisions alone. Future studies need to confirm if some subgroups of patient might benefit from a treat-to-target strategy with ustekinumab., Funding: Janssen-Cilag., Competing Interests: Declaration of interests SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Dr Falk Pharma Eli Lilly, Enthera, Ferring Pharmaceuticals Inc, Gilead, Hospira, Inotrem, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB Inc, and Vifor; and reports payment for expert testimony from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer, and Takeda. SV reports grants or contracts from AbbVie, Johnson & Johnson, Pfizer, Galapagos, and Takeda; consulting fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, and Zealand Pharma; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or education events from AbbVie, Alimentiv, Boehringer Ingelheim, Celgene, Dr Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Janssen, Johnson & Johnson, Pfizer, Takeda, and Tillots Pharma AG. GD'H reports consulting fees from AbbVie, Alimentiv, Arena, AstraZenea, Bristol Myer Squibb, Boehringer Ingelheim, Eli Lilly, Exeliom, Gossamer Bio, Johnson & Johnson, Pfizer, Prometheus, and Protagonist; and payment of honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Myer Squibb, Johnson & Johnson, and Pfizer. JP reports research grants from AbbVie and Pfizer; consulting fees from AbbVie, Arena, Athos, Boehringer Ingelheim, Celgene, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Morphic, Nestle, Origo, Pandion, Pfizer, Progenity, Protagonist, Takeda, Theravance, and Wassermann; reports payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Janssen, Pfizer, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for Alimentiv; and has owner stock options in Oppilan. AD reports consultancy fees from AbbVie, Amgen, BMS/Celgene, Boehringer-Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Fresenius Kabi, Galapagos, Gilead, Janssen, MSD, Lilly, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts, and Vifor; payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events for AbbVie, Falk Foundation, Ferring, Immunowissen.tv, Janssen, Lilly, Med Update GmbH, MSD, Pfizer, Pharmacosmos, Streamed Up, Takeda, Thieme-Verlag, Tillotts, and Vifor. FM has served as a speaker and received honoraria from Merck Sharp & Dohme, AbbVie, Vifor, Falk, Laboratórios Vitória, Ferring, Hospira, and Biogen. MN is an employee of Janssen-Cilag, Polska Sp. z o.o and has stocks or stock options in Johnson & Johnson. MLB is an employee of Janssen-Cilag, France and has stocks or stock options in Janssen. FL is an employees of Janssen-Cilag, France and has restricted share units from Johnson & Johnson. MLa is an employee of Janssen-Cilag, B.V. and has restricted stocks in Janssen. LN is an employee of Janssen-Cilag, Russia. IB is an employee of Janssen-Cilag, Italy. MD reports consulting fees from Bioclinica; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Janssen, Pfizer, Roche, and Takeda; and support for attending meetings and/or travel from AbbVie, Chiesi, Janssen, Mundifarma, SOFAR, Roche, and Takeda. MLu reports no competing interests. AA reports consultancy fees from AbbVie, Allergan, Amgen, Arena, Biogen, Bristol-Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Roche, Samsung Bioepis, Sandoz, and Takeda; payment or honoraria for lecture, presentations, speakers bureaus, manuscript writing, or education events from AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, and Tigenix; research grants from MSD, Takeda, and Pfizer; and support for attending meetings and/or travel from AbbVie, Janssen, Pfizer, and Takeda. MLö has received a research grant from Galapagos and consulting fees from Alimentiv, Bristol Myers Squibb, Galapagos, Gilead, Takeda, and Tillotts. DRG reports consulting fees from Galapagos and Pfizer; payment or honoraria for lectures from AbbVie and Pfizer; and support for attending meetings and travel from AbbVie, Ferring, Janssen, and Tillots. LP-B reports grants or contracts from AbbVie, Fresenius Kabi, MSD, and Takeda; consulting fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Boerhinger Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestle, Inotrem, Enterome, Allergan, MSD, Roche, Arena, Gilead, Hikma, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, Enthera, Theravance, and Pandion Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Galapagos, Janssen, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Arena, Gilead, Hikma, Amgen, and Vifor; support for attending meeting and/or travel from AbbVie, Galapagos, Janssen, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Arena, Gilead, Hikma, Amgen, and Vifor; participation on a Data Safety Monitoring Board or Advisory Board for Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Boerhinger Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestle, Inotrem, Enterome, Allergan, MSD, Roche, Arena, Gilead, Hikma, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, Enthera, Theravance, and Pandion Therapeutics; and stock or stock options in CTMA., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Inflammatory bowel diseases, namely ulcerative colitis and Crohn's disease, occur worldwide and affect people of all ages, with a high impact on their quality of life. Sex differences in incidence and prevalence have been reported, and there are also gender-specific issues that physicians should recognize. For women, there are multiple, important concerns regarding issues of body image and sexuality, menstruation, contraception, fertility, pregnancy, breastfeeding and menopause. This practice-based review focuses on the main themes that run through the life of women with inflammatory bowel diseases from puberty to menopause. Gastroenterologists who specialize in inflammatory bowel diseases and other physicians who see female patients with inflammatory bowel diseases should provide support for these problems and offer adequate therapy to ensure that their patients achieve the same overall well-being and health as do women without inflammatory bowel diseases., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Older age and comorbidities are the main risk factors for adverse COVID-19 outcomes in patients with inflammatory bowel disease (IBD). The impact of IBD medications is still under investigation., Aims: To assess risk factors for adverse outcomes of COVID-19 in IBD patients and use the identified risk factors to build risk indices., Methods: Observational cohort study. Univariable and multivariable logistic regression was used to identify risk factors associated with pneumonia, hospitalisation, need for ventilatory support, and death., Results: Of the 937 patients (446 with ulcerative colitis [UC]) evaluated, 128 (13.7%) had asymptomatic SARS-CoV-2 infection, 664 (70.8%) had a favourable course, and 135 (15.5%) had moderate or severe COVID-19. In UC patients, obesity, active disease and comorbidities were significantly associated with adverse outcomes. In patients with Crohn's disease (CD), age, obesity, comorbidities and an additional immune-mediated inflammatory disease were identified as risk factors. These risk factors were incorporated into two indices to identify patients with UC or CD with a higher risk of adverse COVID-19 outcomes. In multivariable analyses, no single IBD medication was associated with poor COVID-19 outcomes, but anti-TNF agents were associated with a lower risk of pneumonia in UC, and lower risks of hospitalisation and severe COVID-19 in CD., Conclusion: The course of COVID-19 in patients with IBD is similar to that in the general population. IBD patients with active disease and comorbidities are at greater risk of adverse COVID-19 outcomes. IBD medications do not pose additional risks. The risk indices may help to identify patients who should be prioritised for COVID-19 re-vaccination or for therapies for SARS-CoV-2 infection., (© 2021 John Wiley & Sons Ltd.)

Background and Aims: Post-surgical recurrence of Crohn's disease (CD) after ileocolonic resection is common. Early identification of features associated with recurrence is a standard procedure of postoperative management, but the prognostic role of such features when detected at later time points is unclear. We compared the predictivity for Crohn's disease recurrence of common clinical-instrumental variables when assessed early (<12 months) or late (>36 months) after surgery., Methods: This retrospective study considered CD patients who had ileocolonic resection and were followed for a median of 7.6 years. Clinical characteristics, post-surgical therapy, endoscopy recurrence (Rutgeerts' score ≥i2) and ultrasound features were compared between subgroups who had a early or late post-surgical assessment. Univariate and multivariate analyses were done to identify variables associated with recurrence (clinical and surgical)., Results: Of 201 patients, 70 (32%) had a early and 39 (19%) had a late post-surgical assessment. The Early and Late subgroups had similar clinical characteristics. Overall, clinical relapse was observed in 131 patients (66%), surgical relapse in 31 (16%), endoscopic recurrence in 149 (75%) and ultrasonographic recurrence in 132 (66%), without significant differences in frequencies between subgroups. By Cox proportional hazard regression, endoscopic recurrence was a significant predictor of clinical recurrence overall (HR=2.31, P = 0.002) and in the Early (HR=3.85, P = 0.002) but not Late subgroup., Discussion: The most informative postoperative CD assessment is the one done within the first year of surgery. Later endoscopic evaluations have no prognostic value and should be done only for clinical needs or for research purposes., Competing Interests: Declaration of Competing Interest GDP, MM, MM, CR, PM, MC, CR, EM, EE, AL, RR, AF: reported no conflict of interest to disclose CG: Roche boards MD: Advisory board/Lecturer/Grants/Congress participation from Abbvie, Takeda, Janssen, Ferring, MSD, Mundipharma, Pfizer, SOFAR, Chiesi, Roche, Bioclinica, (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: Anti-TNFα agents have been a staple of Crohn's disease treatment for 20 years, but they have weaknesses. New treatments have more recently become available. The aim of this paper is to examine the Crohn's disease patient population for whom anti-TNF treatments are not preferred and where new mechanisms of action should be considered., Methods: A representative sample of 100 Italian physicians with documented expertise with biological treatment of moderate-to-severe Crohn's disease were interviewed. A literature review on Crohn's disease treatment was also conducted to identify patient populations for whom anti-TNFs are unsuitable., Results: On the basis of the interviewed physicians, about 9% of moderate-to-severe Crohn's disease patients were noneligible to anti-TNFα due to contraindication or possible risk of intolerance, while 11% had discontinued anti-TNFα treatment due to complications or intolerance/hypersensitivity. Patients with severe heart disease and at high risk of infections were more frequently considered unsuitable. The proportion of patients considered unsuitable among elderly patients and in those with recurrent infections, cancer, and other comorbidities ranged between 40 and 60%., Conclusions: We provided additional quantitative and qualitative information to help identify patients who are less suitable to anti-TNF agents, who could benefit from newer biologic agents with different mechanisms of action., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives and Study: There is a large interobserver variability in evaluating mucosal lesions of inflammatory bowel disease (IBD), especially in pediatric patients. This multicenter prospective observational study aims to evaluate interobserver agreement (IOA) among pediatric endoscopists in assigning validated IBD endoscopic scores in children., Methods: Fifteen videos of follow-up ileocolonoscopies in children with IBD were recorded and selected as cases. Eleven pediatric endoscopists from different centers blindly evaluated all videos and calculated scores: either Ulcerative Colitis Endoscopic Index of Severity (UCEIS) or Simple Endoscopic Score for Crohn Disease (SES-CD). Scores from all reviewers were compared in order to calculate IOA for general videos and specific sections. Scores from an expert adult reader were used to calculate possible reviewer's characteristics affecting scores' reliability., Results: Intraclass correlation was 0.298 (95% confidence interval [CI]: 0.13-0.55) for ulcerative colitis (UC) and 0.266 (0.11-0.52) for Crohn disease (CD). When a disease activity categorization was adopted (remission, mild, moderate, severe activity) Fleiss kappa coefficient was 0.408 (0.29-0.53) for UC and 0.552 (0.43-0.73) for CD. When stratified by item, vascular pattern of UC was the most reliable item IC: 0.624 (0.321-0.854). In multivariable analysis, none of the reviewer's characteristics affected the readers' errors., Conclusions: This multicenter study shows low agreement among pediatric endoscopists in evaluating endoscopic scores in children with IBD. By using disease activity categorization, agreement slightly increased, mostly for CD. All readers showed a low-grade concordance with the expert adult gastroenterologist's evaluations. Future-specific training programs should be considered to increase IOA in using IBD endoscopic activity scores., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Crohn's disease (CD) and ulcerative colitis, two forms of inflammatory bowel disease (IBD), are chronic and relapsing conditions of the gastrointestinal tract both characterized by long lasting chronic inflammation and increased risk of dysplasia and colorectal cancer (CRC). The aim of our study was to evaluate the interobserver agreement about IBD-associated dysplasia among pathologists belonging to the Italian Group for Inflammatory Bowel Diseases (IG-IBD P)., Methods: The present multicenter survey was performed using telepathology, supported by an open source E-learning platform. Biopsy specimens from 30 colonoscopies and from 20 patients were included. The glass slides of any case, including clinical and endoscopic data, were digitalized and uploaded on the E-learning platform. All the digital slides were grouped in 54 diagnostic "blocks". Blinded histopathological evaluation on all the digital slides was performed by 20 gastrointestinal pathologists. Closed-ended questions about (1) the occurrence of IBD; (2) the classification of IBD (as UC or CD); (3) the presence of active versus quiescent disease; (4) the presence of dysplasia; (5) the possible association of dysplasia with the sites of disease (dysplasia-associated lesion or mass-DALM vs adenoma-like mass-ALM); (6) the grading of dysplasia according to the ECCO guidelines (negative, indefinite, low grade, high grade categories) and (7) the presence of associated serrated features, were proposed in each case. Inter-observer agreement was evaluated by mean agreement percentage and kappa statistic, when suitable., Results: The diagnosis of IBD was confirmed in 19 of 20 patients, 17 of 19 being classified as UC, 2 as CD. The mean interobserver agreement percentages about (1) the evidence of IBD, (2) the presence of either UC or CD and (3) the activity grading resulted to be 80%, 69% and 86%, respectively. Dysplasia was detected in 8/20 patients, with moderate agreement between pathologists (mean 72%, k 0.48). Particularly, low grade dysplasia was found in 13 biopsies (combined k 0.38), whereas high grade dysplasia in 8 (combined k 0.47). When the endoscopic and histopathological data were combined, features consistent with DALM were found in 6 of 20 patients with low grade dysplasia and those consistent with ALM in 2 patients with low grade dysplasia in a single biopsy (mean agreement: 86%). An associated serrated pattern was discovered in 4 patients (7 biopsies)., Conclusions: Our study showed moderate interobserver agreement about the histopathological detection and classification of IBD-associated dysplasia. Further efforts should be undertaken to integrate the histopathological data with both the ancillary tests and molecular investigations.

Background and Aims: Endoscopic assessment of mucosal appearance by independent central reading has become the standard method to assess Crohn's disease activity in clinical trials. The performance characteristics of various endoscopy reading models have yet to be systematically evaluated., Methods: This substudy included patients with Crohn's disease in the exploratory induction cohort of the BERGAMOT trial (NCT02394028) randomly assigned to etrolizumab or placebo. Endoscopies conducted at baseline and week 14 were independently scored using the Simple Endoscopic Score for Crohn's Disease (SES-CD) by a local reader (LR) and 2 central readers (CRs). Five endoscopy reading models were compared: single LR, single CR, average of 2 CRs, and 2 models incorporating the LR and 1 or 2 CRs depending on alignment between the LR and the CR, defined according to a sliding scale applied to a range of scores., Results: Five hundred thirty-five videos were scored. Models involving 2 readers demonstrated lower placebo rates (3.4%) than the single LR (11.9%) and the single CR (6.8%) models. Treatment effect size based on endoscopic improvement (≥50% reduction in SES-CD from baseline) was highest with the 2 models incorporating the LR and 1 or 2 CRs (Δ = 16.2%). Further, in the etrolizumab arm, models with 2 readers demonstrated the lowest variability for the SES-CD., Conclusions: Central endoscopy reading models in Crohn's disease have an impact on placebo response rates and effect size. Incorporating the LR appears to be important because models using both CRs and LRs resulted in the greatest treatment effect size for endoscopic improvement with etrolizumab, lower placebo rates, and reduced variability., (Copyright © 2021. Published by Elsevier Inc.)

This expert-opinion paper reviews available evidence for the use of ustekinumab, a human interleukin 12/23 monoclonal antibody, in the treatment of Crohn's disease and discusses its potential role in the current treatment scenario for the condition. Ustekinumab appears to be associated with rapid and sustained clinical effect, as reported from the clinical research program, with additional support for potential mucosal healing. These characteristics are paralleled by a favorable safety profile, lack of immunogenicity and the presence of systemic anti-inflammatory activity. Importantly, ustekinumab requires only one single intravenous administration, while subsequent dosing is administered subcutaneously, with potential advantages for home-based therapy. Lastly, the dosage of ustekinumab is flexible. On the basis of the evidence, ustekinumab has a role in patients with primary failure or secondary loss of response to anti-tumor necrosis factor agents, as well as in those who have adverse events on front-line biologics or are reinitiating therapy after a treatment holiday. Current evidence suggests that ustekinumab may be particularly suitable in patients who present extra-intestinal manifestations of the disease or are at risk of infections. Ustekinumab may also be considered in the first-line setting, especially in frail patients, in young subjects or in those who have concomitant immune-mediated diseases., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

This paper is the first in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn's disease. Surgical management as well as special situations including management of perianal Crohn's disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016]., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however, neither instrument has been fully validated. We assessed intra-rater and inter-rater reliability of these indices., Design: Video recordings of colonoscopies obtained from 50 patients with CD who participated in an induction trial of a biological therapy were triplicated and reviewed in random order by four central readers. Data were used to assess intra-rater and inter-rater reliability for CDEIS, SES-CD and a global evaluation of lesion severity (GELS). Subsequently, readers participated in a consensus process that identified common sources of disagreement., Results: Intraclass correlation coefficients (ICCs) for intra-rater reliability for CDEIS, SES-CD and GELS (95% CIs) were 0.89 (0.86 to 0.93), 0.91 (0.89 to 0.95) and 0.81 (0.77 to 0.89), respectively, with standard error of measurement (SEM) of 2.10, 2.42 and 1.15. The corresponding ICCs for inter-rater reliability were 0.71 (0.63 to 0.76), 0.83 (0.75 to 0.88) and 0.62 (0.52 to 0.70), with SEM of 3.42, 3.07 and 1.63, respectively. Correlation between CDEIS and GELS was 0.75, between SES-CD and GELS was 0.74 and between CDEIS and SES-CD was 0.92. The most common sources of disagreement were interpretation of superficial ulceration, definition of disease site at the ileocolonic anastomosis, assessment of anorectal lesions and grading severity of stenosis., Conclusions: Central reading of CDEIS and SES-CD had 'substantial' to 'almost perfect' intra-rater and inter-rater reliability; however, the responsiveness of these instruments is yet to be determined., Trial Registration Number: Clinicaltrials.gov NCT01466374., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The difficulties involved in detecting and enumerating Mycobacterium avium subsp. paratuberculosis (MAP) as a pathogen potentially involved in Crohn's disease (CD) are well known. This study aimed to improve this situation through the application of multiple laboratory diagnostic tests to detect and isolate this bacterium from different specimens collected from CD-patients and non-CD subjects as controls. A total of 120 samples (terminal ileum and colon biopsies, blood and stool) were obtained from 19 CD-patients and from 11 individuals who did not have a clinicopathological diagnosis of CD (non-CD controls) attending for ileocolonoscopy. All samples were processed by staining techniques, culture on both solid and liquid media, and Insertion Sequence 900/F57 real-time PCR. The MAP frequency in CD-patients was found in a significantly greater proportion than in non-CD subjects; the most positive samples were biopsies from CD-patients tested by real-time PCR. MAP detection in biopsies, and in the other samples, by applying multiple and validated laboratory diagnostic tests, could be a marker of active infection, supporting MAP involvement in CD.

Background: The diagnosis of inflammatory bowel disease can be challenging and requires the efforts of a multidisciplinary team. We performed a retrospective analysis with the aim of evaluating the adequacy of the prerequisites for arriving at an accurate histological diagnosis., Methods: The following parameters were considered as prerequisites for a diagnosis of inflammatory bowel disease: clinical and endoscopic data; proper sampling and handling of biopsies; and elementary microscopic lesions. We collected 345 cases from 13 centres., Results: The date of onset and treatment were available for 13% and 16% of the cases, respectively. Endoscopy information was accessible for 77% of the cases. Endoscopic mapping was completed in 13% of the cases. In no cases were the biopsies oriented on acetate strips. The diagnosis was conclusive in 47% of the cases. Activity, epithelial disruption and crypt distortion were described in 35% of the reports with a conclusive diagnosis., Conclusion: Our study showed that the diagnostic prerequisites were widely unfulfilled, although approximately half of the diagnoses were conclusive for inflammatory bowel disease. Thus, in our assessment of clinical practice: (1) clinicians seldom provide suitable clinical and/or endoscopic information for a histological diagnosis and (2) histopathological diagnoses of inflammatory bowel disease are often not supported by morphology., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: The long-term risk of neoplasia in Crohn's disease (CD) patients treated with infliximab is undefined. The aim was to assess, in a multicenter, matched-pair study, whether infliximab use in CD is associated with an increased frequency of neoplasia in the long term., Methods: A multicenter, long-term, matched-pair study was conducted in 12 referral inflammatory bowel disease (IBD) centers. An initial cohort of 808 CD patients, including 404 infliximab-treated (CD-IFX) and 404 matched CD controls never treated with infliximab (CD-C) studied from 1999 to 2004, was followed up for an additional 4 years (2004-2008). Cases and controls were matched for: sex, age (±5 years), CD site, follow-up (±5 years), immunosuppressant use, and CD duration (±5 years). From 1999 to 2008 the frequency and characteristics of neoplasia were compared between CD-IFX and CD-C., Results: In 2008, 591 patients (304 CD-IFX, 287 CD-C) were in follow-up. Matched couples included 442 patients: 221 CD-IFX and 221 CD-C (median follow-up, months: 72, range 48-114 versus 75, range 44-114). From 1999 to 2008 the frequency of neoplasia among the 591 patients did not differ between CD-IFX (12/304; 3.94%) and CD-C (12/287; 4.19%; P = 0.95). A comparable frequency of neoplasia was also observed between the 221 matched couples (CD-IFX: 8/221; 3.61% versus CD-C: 9/221; 4.07%; P = 1). No specific histotype of cancer appeared associated with infliximab use., Conclusions: The frequency of neoplasia was comparable in an adult population of CD patients treated or not with infliximab, matched for clinical variables and followed up for a median of 6 years., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

Objectives: Several studies have investigated, with conflicting results, the risk factors for reoperation in Crohn's disease (CD) patients. CARD15 gene variants have been identified as a major genetic risk factor for CD patients and associated with ileal disease, stenosis, and risk of surgery. However, data regarding the association between these variants and the need for reoperation are very few and conflicting. This study evaluated the risk factors of reoperation, including CARD15 gene variants., Methods: A total of 253 consecutive CD patients, recruited in four Italian tertiary-care inflammatory bowel disease (IBD) referral centers, who had submitted to surgery for CD, were included in the study. Clinical characteristics of CD patients, time and main indications for surgery, type of operation, postoperative therapy, and time to second surgery were recorded. CARD15 gene variants were determined by DNA sequencing analysis in each center. Factors related to surgical recurrence, including CARD15 variants, were estimated by Cox proportional hazard regression., Results: In all, 89 patients (35.1%) showed at least one surgical recurrence. Reoperation was significantly correlated with stenosis as indications at initial surgery only. CARD15 variants were found in 36.0% of patients, but did not correlate significantly with the demographic and clinical characteristics of the patients, rate of first surgical recurrence, and time to second operation. CARD15 variants did not significantly affect the reoperation rate, irrespective of indications for surgery., Conclusions: Reoperation for CD is correlated with stenosis at initial surgery, but not with CARD15 gene variants. This finding does not justify more aggressive prophylactic therapy on the basis of CARD15 genotype.

Objective: Abdominal bowel ultrasound (US) is widely used in the management of Crohn's disease (CD). The aim of this study was to evaluate the prognostic role of bowel-wall US morphology on the short-term risk of surgery., Material and Methods: The 147 CD patients recruited in a case-control study comprised 49 cases operated on within 30 days after US examination and 98 matched non-operated controls. Clinical and US characteristics were analysed. Bowel-wall thickness was recorded, bowel-wall patterns were grouped into five types, but for final analysis they were grouped as "preserved" or "disrupted stratification"., Results: Wall thickness and US patterns were significantly different between cases and controls (p<0.0001). A wall thickness >4.5 mm was observed in 45/49 cases and 47/98 controls (OR = 12.21), while "disrupted stratification" was observed in 34/49 cases and 12/98 controls (OR = 16.24). Among the clinical and US characteristics recorded, only 4 US variables were independently associated with surgery (pattern, thickness, presence of fistulae/abscesses and stenoses) and considered for the US score=(2.5*US pattern)+(1.5*Bowel thickness)+(3*Presence of fistulae/abscesses)+(1.5*Presence of stenoses). Based on this score, up to 84% of patients were correctly classified according to actual status (operated/non-operated)., Conclusions: Although it needs further prospective validation, the score we propose seems to be a reliable prognostic marker for the short-term risk of surgery in CD. In particular, the score points out those patients with an impending risk of surgery who need careful and frequent control in order to decide on the right time for surgery.

Background: Infliximab is used for refractory Crohn's disease but there are concerns regarding long-term safety. Recently, JC-polyomavirus (JCV) was studied after 3 cases of progressive multifocal leukoencephalopathy (PML) were found after treatment with natalizumab. The aim of this study was to investigate the short-term effect of infliximab on reactivation of several harmful latent viruses., Methods: Sixty consecutive patients scheduled for infliximab induction course were prospectively enrolled. Blood samples were taken before each infliximab infusion at 0, 2, 6, and 14 weeks. Specific polymerase chain reaction (PCR) analyses were performed to detect JCV, Epstein-Barr virus (EBV), human herpes virus-6, (HHV-6), -7, -8, and cytomegalovirus (CMV)., Results: Indications to infliximab were luminal and fistulizing disease in 49 and 15 cases, respectively. Clinical improvement and remission were achieved in 54 (90%) and 39 (65%) of patients, respectively, at 6 weeks. No patient was JCV-positive at any timepoint. EBV serology was positive for 59/60 patients (98%); EBV-PCR tests were transiently positive (>40 copies/10(5) Peripheral blood mononuclear cells, PBMC) in 4 (7%) patients after infliximab, but in each case were negative at subsequent timepoints. All patients were negative for HHV-6, -7, and -8 at all timepoints. CMV serology was positive in 42 patients (70%), but no CMV-PCR-positive patient was observed. There was no association between concomitant treatments or clinical characteristics and viral status., Conclusions: Our results support the safety of short-term infliximab treatment with respect to latent virus reactivation. The long-term effects of infliximab, particularly for the issue of lymphoproliferative disorders, warrants further studies with larger populations, but so far data are reassuring.

Background and Aim: Inflammatory bowel diseases (IBD) commonly affect women during the reproductive years. The aim of the present study was to evaluate the reproductive histories of patients with ulcerative colitis (UC) and Crohn's disease (CD) considering pregnancies occurring before and after the diagnosis., Method: Case-control study evaluating IBD patients, interviewed by questionnaire about outcome of pregnancy and course of disease., Results: A total of 502 pregnancies from 199 patients in the prediagnosis group and 121 pregnancies from 90 patients in the post-diagnosis group were respectively compared with 996 and 204 pregnancies recorded in a control population. In prediagnosis pregnancies, CD was associated with increased risk of preterm delivery (odds ratio [OR] 4.62, 95% confidence interval [CI] 2.77-7.73; P < 0.001 vs controls and OR 3.52, 95% CI 1.75-7.07; P < 0.001 vs UC) and lower birthweight (P < 0.001 vs UC and controls). In post-diagnosis pregnancies, the rate of live births was lower, but not statistically significant in IBD (OR 0.22, 95% CI 0.04-1.25; P = 0.08) and the birthweight was significantly lower in CD than in UC (P < 0.03) and in controls (P < 0.02). In post-diagnosis pregnancies, a higher incidence of congenital abnormalities was found in IBD patients (5.5% vs 0.0%). The spontaneous abortion rate and therapeutic abortions were significantly higher in post than in prediagnosis pregnancies. Neither disease activity at conception nor treatment appeared to influence the outcome of pregnancy., Conclusions: CD in the preclinical phase has some influence on pregnancy. In patients with IBD our data suggest that conception should not be discouraged. However, because of a modest increase in mild congenital abnormalities and abortions rates, pregnancy in IBD patients should be closely monitored.

Crohn's disease (CD) is a chronic inflammatory disorder which may involve any part of gastrointestinal tract. Chronic inflammation is primarily due to an immunological imbalance between pro- and anti-inflammatory cytokines, and with a defective apoptosis of lamina propria T cells. Amongst the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) seems to play a central role in pathogenesis of CD. Over the last years, increasing knowledge on the pathogenesis of CD together with progresses in bio-technology have led to the development of a number of biological agents targeting specific molecules involved in gut inflammation, most importantly TNF-alpha and its receptors. The aim of this paper is to critically review the rationale and state-of-the art for the use TNF- alpha inhibitors in the treatment of CD.

The medical management of inflammatory bowel disease (IBD) has changed considerably since the advent of biologic treatments. In this review we offer a critical evaluation of controlled studies with biologic agents for the management of both Crohn's disease (CD) and ulcerative colitis (UC). Biologics under evaluation or approved for UC that are discussed include monoclonal antibodies to tumor necrosis factor ([TNF]) infliximab), inhibitors of adhesion molecules (MLN02 and alicaforsen), anti-CD3 antibodies (visilizumab), and anti-interleukin (IL)-2 receptor antibodies (daclizumab). Biologics under evaluation or approved for CD that are reviewed include three monoclonal antibodies to TNF (infliximab, adalimumab, and certolizumab pegol), monoclonal antibodies against IL-12, interferon-chi, and IL-6 receptors, inhibitors of adhesion molecules (natalizumab, alicaforsen), and growth factors. Only the chimeric monoclonal anti-TNF antibody infliximab is currently available worldwide. The potency of this agent in moderate-to-severe UC and CD has been one of the most important advances in the care of IBD in the past decade.

Background: Healing of mucosal lesions appears to offer significant benefit and is an important end point in clinical trials of treatment for Crohn's disease. The only validated endoscopic activity score at present is the Crohn's Disease Endoscopic Index of Severity, which is complicated and time consuming and, hence, is unsuitable for routine use. The aim of this study was to develop and to prospectively validate a simpler endoscopic score of disease activity, the Simple Endoscopic Score for Crohn's Disease., Methods: Selected endoscopic parameters (ulcer size, ulcerated and affected surfaces, stenosis) were scored from 0 to 3. Reproducibility for scoring of these parameters was evaluated through 71 examinations in which the endoscopist was paired with an observer. The simplest score (Simple Endoscopic Score for Crohn's Disease) that was highly correlated with both the Crohn's Disease Endoscopic Index of Severity and Crohn's Disease Activity Index was derived for 70 patients and then was prospectively validated in 121 different patients with Crohn's disease., Results: The interobserver agreement for all selected endoscopic variables was excellent (kappa coefficient 0.791-1.000). Based on multiple linear regression, the Simple Endoscopic Score for Crohn's Disease resulted in the sum of the scores for ulcer size, ulcerated surface, affected surface, and luminal narrowing. In the validation phase of the study, a strong correlation was demonstrated for the Simple Endoscopic Score for Crohn's Disease with Crohn's Disease Endoscopic Index of Severity (r = 0.920). In addition, the Simple Endoscopic Score for Crohn's Disease was correlated to clinical parameters and serum C-reactive protein level., Conclusions: Simple Endoscopic Score for Crohn's Disease is a simple, reproducible, and easy-to-use endoscopic scoring system for Crohn's disease.

A global measurement of Crohn's disease activity, comprising clinical, endoscopic, biochemical and pathological features is not available yet and perhaps is unobtainable. In this review we analyse the most used and validated clinical indices (Crohn's Disease Activity Index [CDAI], Perianal Disease Activity Index [PDAI], fistula drainage assessment), quality of life scores (Inflammatory Bowel Disease Questionnaire [IBDQ]), sub-clinical markers (C-reactive protein, faecal calprotectin, intestinal permeability) and endoscopic indices (Crohn's Disease Endoscopic Index of Severity [CDEIS]/Simple Endoscopic Score for Crohn's Disease [SES-CD], Rutgeeerts' score for postsurgical recurrence). We also review the main advantages and disadvantages of each of these scoring systems. All these indices are rather complex and time-consuming, therefore their use is limited to clinical trials. In everyday clinical practice most gastroenterologists rely on their global clinical judgement, which is less reproducible, but simpler for decision-making.

Management of Crohn's disease has changed considerably in recent years. The discovery of tumor necrosis factor (TNF) as a pivotal cytokine in the inflammatory cascade has led to the development of several neutralizing antibodies, soluble receptors, and small molecules, interfering with TNF gene transcription and expression. Infliximab is the only monoclonal antibody that is commercially available. This potent molecule is effective for both active and fistulizing disease in the acute and maintenance phases of treatment. In addition to anti-TNF agents, weekly methotrexate injection and the classic "antimetabolites" azathioprine and 6-mercaptopurine remain highly valuable as maintenance drugs. "Tailored" antimetabolite therapy has now become possible with metabolite measurements and determination of the TPMT gene. The active metabolite thioguanine itself could be a promising alternative in patients who are intolerant of 6-mercaptopurine. In fistulizing disease, infliximab is becoming the treatment of choice, although fistula tracks do not disappear permanently and many patients still need surgical intervention.

Background: In the past few years, serologic markers have been proposed in inflammatory bowel disease. Anti-Saccharomyces cerevisiae antibodies showed high specificity for Crohn's disease. A prognostic role for serology has also been hypothesised., Aims: To evaluate anti-Saccharomyces cerevisiae antibody distribution in an unselected Italian inflammatory bowel disease population. To analyse whether anti-Saccharomyces cerevisiae antibody status (positive/negative) and/or anti-Saccharomyces cerevisiae antibody titres are associated with clinical variables and outcome measures in Crohn's disease patients., Patients and Methods: A series of 299 inflammatory bowel disease patients were evaluated; serum samples were taken and a short clinical history was recorded. anti-Saccharomyces cerevisiae antibodies IgG enzyme-linked immunosorbent assay Medilab (Milan, Italy) kit was used in order to determine anti-Saccharomyces cerevisiae antibody status., Results: Sensitivity, specificity and likelihood ratio for positive test in the differential diagnosis of inflammatory bowel disease was 59%, 89%, 8.1, respectively. Clinical variables significantly associated with anti-Saccharomyces cerevisiae antibody status in logistic regression were found to be ileal location (p=0.01) and earlier age at diagnosis (p<0.01). Among ileal Crohn's disease patients, there was a trend in concordance between anti-Saccharomyces cerevisiae antibody titres and higher number of surgical procedures which was not statistically significant applying more complex statistics., Conclusions: In an Italian inflammatory bowel disease population, anti-Saccharomyces cerevisiae antibodies status showed characteristics similar to those previously reported. Anti-Saccharomyces cerevisiae antibody positivity is associated with ileal involvement and with earlier onset of Crohn's disease.