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Background: Interleukin-23 inhibition is effective in treating ulcerative colitis. Guselkumab is a dual-acting, human IgG1, interleukin-23p19 subunit inhibitor that potently neutralises interleukin-23 and can bind to CD64. We aimed to evaluate the efficacy and safety of guselkumab as induction and maintenance therapy in patients with ulcerative colitis., Methods: The primary populations of these two phase 3, randomised, double-blind, placebo-controlled studies (QUASAR phase 3 induction and maintenance) included randomised and treated adults with moderately to severely active ulcerative colitis (induction baseline modified Mayo score from 5 to 9) with inadequate response or intolerance to conventional or advanced ulcerative colitis therapy. Patients were randomly assigned (3:2) to receive guselkumab 200 mg given intravenously or placebo at weeks 0, 4, and 8 (phase 3 induction study). All patients were randomly assigned using web-based interactive response technology. Patients in clinical response 12 weeks after guselkumab induction given intravenously (from QUASAR phase 2b and phase 3 induction studies) were randomly assigned (1:1:1) at maintenance week 0 to guselkumab 200 mg given subcutaneously every 4 weeks or 100 mg every 8 weeks or placebo for 44 weeks (maintenance). Primary endpoints were clinical remission at induction week 12 and maintenance week 44. This study is registered with ClinicalTrials.gov, NCT04033445., Findings: The induction study primary population included 701 patients (guselkumab 200 mg given intravenously 60% [421 patients]; placebo 40% [280 patients]). The maintenance study primary population included 568 guselkumab induction responders randomly assigned to receive guselkumab 200 mg given subcutaneously every 4 weeks (190 [33%] patients) or 100 mg every 8 weeks (188 [33%] patients) or placebo (guselkumab withdrawal 190 [33%] patients). A significantly greater proportion of patients treated with guselkumab given intravenously had clinical remission at induction week 12 (23% [95 of 421 patients]) than did placebo-treated patients (8% [22 of 280 patients]; adjusted treatment difference 15%, 95% CI 10-20; p<0·0001). Clinical remission at maintenance week 44 was achieved by a significantly greater proportion of patients treated with guselkumab 200 mg given subcutaneously every 4 weeks (50% [95 of 190 patients]; adjusted treatment difference 30%, 95% CI 21-38; p<0·0001) and 100 mg every 8 weeks (45% [85 of 188 patients]; adjusted treatment difference 25%, 16-34; p<0·0001) than with placebo (19% [36 of 190 patients]). The overall safety profile was favourable and consistent with that of guselkumab in approved indications. In the induction study, adverse events were reported by 49% of patients in both groups (208 of 421 guselkumab-treated patients and 138 of 280 placebo-treated patients), serious adverse events were reported by 3% (12 of 421) of guselkumab-treated patients and 7% (20 of 280) of placebo-treated patients, and adverse events leading to treatment discontinuation were reported by 2% (seven of 421) of guselkumab-treated patients and 4% (11 of 280) of placebo-treated patients. In the maintenance study, adverse event rates were similar among groups, and the most frequently reported adverse events in all groups were ulcerative colitis, COVID-19, and arthralgia. No active tuberculosis, anaphylaxis, serum sickness, or clinically important hepatic disorders were reported in either study., Interpretation: Guselkumab was effective and safe as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis., Funding: Janssen Research and Development., Competing Interests: Declaration of interests DTR reports consulting, speaker fees, and advisory board participation for AbbVie, Altrubio, Apex, Avalo, Bristol Myers Squibb, Buhlmann Diagnostics, Celgene, Connect BioPharma, Iterative Health, Janssen (Johnson & Johnson), Lilly, Pfizer, Samsung Neurologica, and Takeda; Altrubio, Datos Health, and Iterative Health stock options; grants from Takeda; and is on the Board of Directors of Cornerstones Health and on the Crohn's & Colitis Foundation's Board of Trustees. JRA reports research support from Merck and Pfizer; consulting and speaker fees from AbbVie, Artugen Therapeutics, Bristol Myers Squibb, Ferring, Finch Therapeutics, Iterative Scopes, Janssen, Merck, Pfizer, and Seres Therapeutics; and is a steering committee member and investigator for Janssen. JP reports consulting fees from AbbVie, Alimentiv, Athos, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech (a subsidiary of Roche), GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonis, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman; and fees for data safety monitoring board or advisory board participation from Alimentiv, Sanofi, Sorriso, and Surrozen. NS, SSY, K-HGH, MG, RW, HZ, and JJ are employees of Janssen Research & Development, which is a wholly owned subsidiary of Johnson & Johnson, and might own stock in Johnson & Johnson. BGF reports consulting and speaker fees from AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital Advisors, Atomwise, BioJamp, Biora (Progenity), Boehringer-Ingelheim, Boxer, Business Intelligence Pharma, Celsius Therapeutics, Celgene (a subsidiary of Bristol-Myers Squibb), Connect BioPharma, Cytoki Pharma, Disc Medicine, Duality, EcoR1 Capital, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech (a subsidiary of Roche), Gilead, Gossamer Bio, GlaxoSmithKline, Hinge Bio, Hot Spot Therapeutics, Imhotex, Immunic Therapeutics, InDex Pharmaceuticals, JAKAcademy, Janssen, Japan Tobacco, Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, LifeSci Capital, Lilly, Lument AB, Millennium, MiroBio, Morphic Therapeutic, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, PlayToKnow AG, Prometheus Therapeutics and Diagnostics, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX Pharma, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen, Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHsquared, Viatris, Ysios, Ysopia, and Zealand Pharma; payment for expert testimony from Morgan Lewis and Lenczner Slaght; support for meeting attendance and travel from AbbVie, Business Intelligence Pharma, Janssen, Pfizer, and Takeda; data safety monitoring board or advisory board participation for AbbVie, Amgen, AMT Pharma, AnaptysBio, Axio Research, Biora (Progenity), Boehringer-Ingelheim, Celgene, EcoR1 Capital, Genentech (a subsidiary of Roche), GlaxoSmithKline, InDex Pharmaceuticals, Janssen, Lilly, MiroBio, Morphic Therapeutic, Origo BioPharma, Pfizer, Prometheus Biosciences, REDX Pharma, Sanofi, Takeda, Teva, and Tillotts; and stock or stock option ownership in Gossamer Bio. TH reports research grants from AbbVie, Boston Scientific, Daiichi-Sankyo, EA Pharma Co, JIMRO Co, Mitsubishi Tanabe Pharma Corporation, Kissei Pharmaceutical, Kyorin Pharmaceutical Co, Mochida Pharmaceutical Co, Nippon Kayaku Co, Pfizer, Takeda Pharmaceutical Co, Zeria Pharmaceutical Co; and consulting fees and honoraria from AbbVie GK, Bristol Myers Squibb, EA Pharma Co, Gilead Sciences, Janssen Pharmaceutical, Kyorin Pharmaceutical Co, Lilly, Mitsubishi Tanabe Pharma Corp, Nichi-Iko Pharmaceutical Co, Pfizer, Takeda Pharmaceutical Co, and Zeria Pharmaceutical Co. GRL reports consulting fees, speaker fees, and meeting attendance or travel support from AbbVie, Allergan, American Gastroenterological Association, American Regent (Creative Educational Concepts), Amgen (continuing medical education sponsor), Boehringer Ingelheim (continuing medical education sponsor), Bristol Meyers Squibb, Celgene, Exact Sciences (continuing medical education sponsor), Ferring, Focus Medical Communications, Gilead, IBD Horizon, Ironwood, Janssen (continuing medical education sponsor), Janssen Biotech (continuing medical education sponsor), Janssen Orthobiotech, Janssen Scientific (continuing medical education sponsor), Lilly, MedEd Consultants, Pennsylvania Society of Gastroenterology, Pfizer, Pharmacosmos, Physician Education Resource, Prometheus Laboratories, Salix (continuing medical education sponsor), Sandoz, Sanofi (continuing medical education sponsor), Seres Pharmaceuticals (continuing medical education sponsor), Takeda, UCB, and Vindico; research support from Bristol Meyers Squibb, Celgene, Janssen Orthobiotech, Pfizer, Takeda, and UCB; data safety monitoring board participation with Lilly; honoraria from Gastroenterology and Hepatology (Gastro-Hep Communications; editor), Springer Science and Business Media (editor), and Up-To-Date-Walters Kluwer (author); royalties from SLACK (book royalty) and Professional Communications (textbook royalty); and Chair, Professional Education Committee and Member of the National Scientific Advisory Committee for Crohn's Colitis Foundation. BB reports consulting and speaker fees from AbbVie, Alimentiv, Amgen, Bausch Health, BioJamp Pharma, Bristol Myers Squibb, Celgene, Celltrion, Eupraxia, Ferring, Fresenius Kabi, Gilead, Iterative Health, Janssen, Lifelabs, Lilly, Merck, Mylan, Novartis, Organon, Pendopharm, Pfizer, Sandoz, Takeda, and Viatris; serves on a data safety monitoring board or advisory board for Eupraxia; and owns Qu Biologic stock. LP-B reports grants or contracts from Celltrion, Fresenius Kabi, Medac, Merck Sharp & Dohme, and Takeda; consulting and payment or honoraria and data safety monitoring board or advisory board participation for AbbVie, Abivax, Adacyte, Alfasigma, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Kern Pharma, Lilly, Medac, Mopac, Morphic, Merck Sharp & Dohme, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, and Ysopia; and meeting attendance and travel support from AbbVie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen, Lilly, Medac, Morphic, Merck Sharp & Dohme, Pfizer, Sandoz, Takeda, Thermo Fischer, and Tillots. BES reports medical writing support from AbbVie, Abivax, Bristol Myers Squibb, Celltrion, Janssen (a subsidiary of Johnson & Johnson), Lilly, Merck, Pfizer, and Takeda; institutional grants or contracts from Bristol Myers Squibb and Janssen (a subsidiary of Johnson & Johnson); consulting fees and payment or honoraria and data safety monitoring board or advisory board participation for AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celgene, Celltrion, ClostraBio, Equilium, Enthera, Enveda Biosciences, Evommune, Ferring, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, Glaxo SmithKline, Gossamer Bio, Imhotex, Immunyx Pharmaceuticals, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Johnson & Johnson, Kaleido, Kallyope, Lilly, Merck, Microbiotics, Mitsubishi Tanabe, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Palisade Bio, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Therapeutics, Spyre Therapeutics, Sun Pharma, Surrozen, Takeda, Target RWE, Teva, Theravance Biopharma, TLL Pharmaceutical, Tr1X, Union Therapeutics, and Ventyx Bioscience; meeting attendance and travel support from Janssen, Lilly, Mitsubishi Tanabe, and Pfizer; and stock in Ventyx Bioscience. AD reports consulting and speaker fees from AbbVie, Abivax, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene (a subsidiary of Bristol Myers Squibb), Celltrion, Falk Foundation, Ferring, Fresenius Kabi, Galapagos, Gilead, High5MD, Janssen, Lilly, Materia Prima, MedToday, Novartis, Pfizer, Pharmacosmos, Roche (a subsidiary of Genentech), Sandoz, Sandoz (a subsidiary of Hexal), Streamed-Up, Takeda, Tillotts, and Vifor and payment for manuscript preparation from Biogen, Falk Foundation, Janssen, Takeda, and Thieme., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background & Aims: Evaluating cardiovascular safety of sphingosine 1-phosphate (S1P) receptor modulators is warranted due to S1P receptor expression on cardiomyocytes and vascular endothelial cells. This analysis reports the cardiovascular safety of ozanimod, an S1P receptor modulator, in patients with moderately to severely active ulcerative colitis from the phase 3 True North (TN) and open-label extension (OLE)., Methods: All patients who received ozanimod in TN (n = 796) and all eligible TN patients who entered the OLE (n = 823) were included. Cardiovascular-related adverse events were evaluated in patients with up to 146 weeks of ozanimod exposure (2219 patient-years), which included 52 weeks during TN., Results: On TN day 1, first-dose ozanimod resulted in a 0.2 beats per minute mean decrease in heart rate from pretreatment to hour 6; 2 patients experienced bradycardia, which resolved without treatment modification. Mean systolic and diastolic blood pressure increases of 5.1 and 2.2 mm Hg, respectively, were observed at TN week 52. No second-degree Mobitz type II atrioventricular block events were reported; 1 third-degree atrioventricular block unrelated to ozanimod occurred in the OLE. Cardiac and vascular treatment-emergent adverse events were infrequent (3.8% [31 of 823] and 8.5% [70 of 823]); no ozanimod-related cardiovascular deaths occurred. The incidences of deep-vein thrombosis (0.2%; 2 of 823), pulmonary embolism (0.2%; 2 of 823), and ischemic stroke (0.4%; 3 of 823) in the OLE were low., Conclusions: No new cardiovascular safety signals were identified, consistent with findings from previous ozanimod studies. There were few major adverse cardiovascular events or thromboembolic events, which were unrelated or unlikely related to ozanimod. Ozanimod has a well-tolerated cardiovascular safety profile when prescribed in accordance with the label. Clinical trial registry website and trial numbers: ClinicalTrials.gov numbers: NCT02435992 and NCT02531126., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: The QUASAR Phase 2b Induction Study evaluated the efficacy and safety of guselkumab, an interleukin-23p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) with prior inadequate response and/or intolerance to corticosteroids, immunosuppressants, and/or advanced therapy., Methods: In this double-blind, placebo-controlled, dose-ranging, induction study, patients were randomized (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0/4/8. The primary endpoint was clinical response (compared with baseline, modified Mayo score decrease ≥30% and ≥2 points, rectal bleeding subscore ≥1-point decrease or subscore of 0/1) at week 12. Guselkumab and placebo week-12 clinical nonresponders received subcutaneous or intravenous guselkumab 200 mg, respectively, at weeks 12/16/20 (uncontrolled study period)., Results: The primary analysis population included patients with baseline modified Mayo scores ≥5 and ≤9 (intravenous guselkumab 200 mg, n = 101; 400 mg, n = 107; placebo, n = 105). Week-12 clinical response percentage was greater with guselkumab 200 mg (61.4%) and 400 mg (60.7%) vs placebo (27.6%; both P < .001). Greater proportions of guselkumab-treated vs placebo-treated patients achieved all major secondary endpoints (clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization) at week 12. Among guselkumab week-12 clinical nonresponders, 54.3% and 50.0% of patients in the 200- and 400-mg groups, respectively, achieved clinical response at week 24. Safety was similar among guselkumab and placebo groups., Conclusions: Guselkumab intravenous induction was effective vs placebo in patients with moderately to severely active UC. Guselkumab was safe, and efficacy and safety were similar between guselkumab dose groups., Clinicaltrials: gov number: NCT04033445., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis., Aim: To report efficacy and infection rates in patients receiving tofacitinib induction treatment, by baseline corticosteroid status., Methods: We evaluated efficacy and safety data from OCTAVE Induction 1&2 in patients with moderately-to-severely active ulcerative colitis who received tofacitinib 10 mg twice daily or placebo for 8 weeks, based on induction baseline oral corticosteroid use (Corticosteroid-Yes/No) and dose (< 20/ ≥ 20 mg/day). Infections of interest included serious infections, herpes zoster (HZ), and adjudicated opportunistic infections (OIs)., Results: At OCTAVE Induction 1&2 baseline, 478/1092 (43.8%) patients were receiving corticosteroids. Tofacitinib demonstrated significant induction efficacy versus placebo for both Corticosteroid-Yes and Corticosteroid-No. With adjustment for prior tumor necrosis factor inhibitor and immunosuppressant failure, there were no statistically significant differences in remission and clinical response rates for Corticosteroid-Yes versus Corticosteroid-No. Among tofacitinib-treated patients, HZ and OIs occurred more frequently in Corticosteroid-Yes versus Corticosteroid-No, regardless of dose (< 20 mg vs. ≥ 20 mg). Infection incidence rates (regardless of severity/seriousness) during tofacitinib induction were generally similar regardless of baseline corticosteroid use. The proportion of tofacitinib-treated patients with HZ was 0.2% for Corticosteroid-No versus 1.1% for Corticosteroid-Yes < 20 mg and 1.0% for Corticosteroid-Yes ≥ 20 mg. Two out of three patients had HZ OIs., Conclusions: Tofacitinib induction efficacy (clinical response and remission) was similar in baseline corticosteroid subgroups. Infections of interest were rare; HZ and OIs occurred more frequently among those receiving tofacitinib and corticosteroids versus those receiving tofacitinib without corticosteroids., Trial Registration: http://www., Clinicaltrials: gov (NCT01465763[21/10/2011]; NCT01458951[21/10/2011])., (© 2023. The Author(s).)

Background: In patients with ulcerative colitis (UC), risks of infection and malignancies increase with age. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. This analysis assessed age as a risk factor for adverse events of special interest (AESI) in the tofacitinib UC clinical program., Methods: Data were from phase 2 and 3 induction studies, a phase 3 maintenance study, and an open-label, long-term extension study. Efficacy and/or safety outcomes were analyzed in the Induction, Maintenance, and Overall Cohorts (patients who received ≥ 1 dose of tofacitinib), stratified by age. The effects of baseline demographic and disease-related factors on AESI incidence were assessed by Cox proportional-hazards regression analysis., Results: In the Overall Cohort (1157 patients with ≤ 6.8 years' tofacitinib treatment), age was a statistically significant predictor of herpes zoster (HZ), malignancies excluding nonmelanoma skin cancer (NMSC), and NMSC. Other statistically significant predictors included prior tumor necrosis factor inhibitor failure for HZ, NMSC, and opportunistic infection events, and prior duration of UC for malignancies excluding NMSC. In the Induction and Maintenance Cohorts, a higher proportion of tofacitinib-treated than placebo-treated patients (numerical difference) achieved the efficacy endpoints (endoscopic improvement, clinical remission, clinical response) across all age groups., Conclusions: Older individuals receiving tofacitinib as induction and maintenance therapy to treat UC may have an increased risk of HZ, malignancies (excluding NMSC), and NMSC versus similarly treated younger patients, consistent with findings from the general population. Across all age groups, tofacitinib demonstrated greater efficacy than placebo as an induction and maintenance therapy., Clinicaltrials.gov Registration Numbers: NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612., (© 2022 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to estimate the overall incidence of safety events in patients with UC in a real-life population cohort for comparison with the tofacitinib UC clinical trial program., Methods: Clinical trial-like criteria were applied to an IBM MarketScan® claims database population-based cohort (n = 22,967) of patients with UC (October 2010 to September 2015) to identify a UC trial-like cohort treated with tumor necrosis factor inhibitors (TNFi; n = 6366) to compare with the tofacitinib UC clinical trial cohort (n = 1157)., Results: Incidence rates (events per 100 patient-years; [95% confidence interval]) in the UC trial-like cohort were as follows: serious infections, 3.33 (2.73-4.02); opportunistic infections (OIs; excluding herpes zoster [HZ]), 1.45 (1.06-1.93); HZ, 1.77 (1.34-2.29); malignancies (excluding nonmelanoma skin cancer [NMSC]), 0.63 (0.43-0.90); NMSC, 1.69 (1.35-2.10); major adverse cardiovascular events (MACE), 0.51 (0.31-0.79); pulmonary embolism (PE), 0.54 (0.30-0.89); deep vein thrombosis (DVT), 1.41 (1.00-1.93); and gastrointestinal perforations, 0.31 (0.16-0.54). Compared with the UC trial-like cohort, tofacitinib-treated patients had numerically lower incidence rates for serious infections (1.75 [1.27-2.36]), OIs (excluding HZ; 0.16 [0.04-0.42]), NMSC (0.78 [0.47-1.22]), PE (0.16 [0.04-0.41]), and DVT (0.04 [0.00-0.23]), and a higher rate for HZ (3.57 [2.84-4.43]); rates for malignancies (excluding NMSC), MACE, and gastrointestinal perforations were similar., Conclusions: When acknowledging limitations of comparing claims data with controlled clinical trial data, incidence rates for HZ among TNFi-treated patients in the UC trial-like cohort were lower than in the tofacitinib UC clinical trial cohort; rates for serious infections, OIs, NMSC, PE, and DVT were numerically higher., Clinicaltrials.gov: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we performed an integrated analysis of malignancy events from the tofacitinib phase 3 UC clinical development program (excluding nonmelanoma skin cancer [NMSC])., Methods: Data (up to May 2019) were pooled from two phase 3 induction studies, a phase 3 maintenance study, and an ongoing, open-label, long-term extension (OLE) study, and analyzed as 3 cohorts: induction (N = 1139), maintenance (N = 592), and overall (induction, maintenance, and ongoing OLE study; N = 1124). Proportions and incidence rates (IRs; unique patients with events per 100 patient-years [PY] of exposure) for malignancies confirmed by adjudication were calculated., Results: The overall cohort consisted of patients who received at least 1 dose of tofacitinib at 5 or 10 mg twice daily, for up to 6.8 years, with an exposure of 2576.4 PY. Of the 1124 overall cohort tofacitinib-treated patients, 20 developed a malignancy (excluding NMSC; IR, 0.75; 95% confidence interval, 0.46-1.16), of which 17 occurred in patients treated with tofacitinib 10 mg twice daily; importantly, more than 80% of patients predominantly received this dose. Furthermore, there was no apparent clustering of malignancy types, and IRs were stable over time., Conclusions: In the tofacitinib UC clinical development program, malignancy events were infrequent, and rates were comparable with those in the tofacitinib rheumatoid arthritis and psoriatic arthritis clinical development programs, and for biologic UC treatments. ClinicalTrials.gov: NCT01465763, NCT01458951, NCT01458574, and NCT01470612., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background & Aims: Understanding the burden of Crohn's disease (CD) and ulcerative colitis (UC) is important for measuring treatment value. We estimated lifetime health care costs incurred by patients with CD or UC by age at diagnosis., Methods: We collected data from 78,620 patients with CD, 85,755 with UC, and propensity score-matched control subjects from the Truven Health MarketScan insurance claims databases (2008‒2015). Total medical (inpatient, outpatient) and pharmacy costs were captured. Cost variations over a lifetime were estimated in cost-state Markov models by age at diagnosis, adjusted to 2016 U.S. dollars and discounted at 3% per annum. We measured lifetime total and lifetime incremental cost (the difference between costs of CD or UC patients vs matched controls)., Results: For CD, the lifetime incremental cost was $707,711 among patients who received their diagnosis at 0‒11 years, and $177,614 for patients 70 years or older, averaging $416,352 for a diagnosis at any age. Lifetime total cost was $622,056, consisting of outpatient ($273,056), inpatient ($164,298), pharmacy ($163,722), and emergency room (ER) ($20,979) costs. For UC, the lifetime incremental cost was $369,955 among patients who received their diagnosis at 0‒11 years, and $132,396 for individuals 70 years or older, averaging $230,102 for a diagnosis at any age. Lifetime total cost was $405,496, consisting of outpatient ($163,670), inpatient ($123,190), pharmacy ($105,142), and ER ($13,493) costs. Therefore, the prevalent populations of patients with CD or UC in the United States in 2016 are expected to incur lifetime total costs of $498 billion and $377 billion, respectively., Conclusions: Using a Markov model, we estimated lifetime costs for patients with CD or UC to exceed previously published estimates. Individuals who receive a diagnosis of CD or UC at an early age (younger than 11 years) incur the highest lifetime cost burden. Advancing management strategies may significantly improve patient outcomes and reduce lifetime health care spending., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Hospitalizations contribute significantly to the annual health care expenditure for inflammatory bowel disease (IBD), and reducing cost of care without compromising outcomes is a rising priority. Teaching hospitals (THs) have higher costs and utilize trainees in care to a greater extent than community hospitals, and it is unknown how hospital teaching status (HTS) affects outcomes. We therefore sought to investigate the impact of HTS on IBD hospitalization outcomes., Methods: We used the Vizient clinical database to identify patients hospitalized between October 1, 2014, and March 31, 2018, for IBD. Vizient hospitals were divided into major THs, minor THs, and non-THs. We used multivariable linear regression of aggregated discharge data to assess the association of HTS with mean length of stay (LOS), mean direct cost (DC), 30-day readmission rate (RR), and in-hospital mortality rate (MR), while adjusting for demographics and disease complexity., Results: Vizient included 29,863 discharges among 291 hospitals for ulcerative colitis (UC) and 62,698 discharges among 314 hospitals for Crohn's disease (CD) between October 1, 2014, and March 31, 2018. Unadjusted mean LOS, mean DC, and 30-day RR were greater among THs for both UC and CD. Unadjusted MR was greater among major THs for UC but not CD. After multivariable analysis, only 30-day RR for UC was increased in major THs relative to non-THs (1.98%; 95% confidence interval, 0.33%-3.61%)., Conclusions: Differences in metrics of cost-effective hospital care for patients with IBD appear to be driven by disease severity rather than HTS. Future research should attempt to better characterize factors driving resource utilization for IBD hospitalizations., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Many patients with ulcerative colitis (UC) fear the potential side effects of immunosuppressive therapies. However, those with medically refractory disease often require total proctocolectomy (TPC) with a permanent ostomy or pouch, which may reduce quality of life. Prior studies have identified TPC predictors; however, no clinically useful prognostic tools exist to guide shared therapeutic decision-making. We therefore sought to develop a prediction tool of future TPC risk in UC patients., Methods: In this retrospective study, clinic charts of UC patients were reviewed from January 1, 2017, to December 31, 2017. Cases had TPC performed for refractory UC after January 1, 2008. Controls had no prior UC surgery. Clinical data were assessed 1-12 months preceding TPC or clinic visit for cases and controls, respectively. We randomly selected two-thirds of patients to develop a TPC prediction model using multivariable logistic regression. One-third was reserved for model validation., Results: We identified 115 cases and 325 controls. TPC predictors included albumin, 9-point Mayo score >5, Mayo endoscopic subscore >1, and corticosteroid use within 6 months. The areas under the receiver operating characteristic curve for the multivariable model were 0.94 (95% confidence interval [CI], 0.92-0.95) and 0.92 (95% CI, 0.89-0.95) for the test and validation cohorts, respectively. The validation cohort demonstrated a significant difference in calculated probability distributions between patients who did and did not have TPC (P < 0.01). We incorporated our model into a web-based application to allow convenient calculation of a patient's TPC risk., Conclusions: We created a user-friendly tool to assess TPC risk in UC. Prospective assessment will determine its utility for shared therapeutic decision-making., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Thiopurines (azathioprine, mercaptopurine, thioguanine) and methotrexate are widely used in a variety of clinical management scenarios for ulcerative colitis and Crohn's disease. With the introduction of biologic therapies over the last 2 decades, controversies have emerged as to how these immunomodulators should be used in clinical practice, either alone as monotherapies or in combination with biologic therapies. Here, we provide a summary of evidence and our interpretations regarding how physicians can or should incorporate these agents into clinical practice. We have organized the review into sections regarding their utility as monotherapy or as combination therapy with biologics and safety considerations. Clinical pharmacologic considerations are important regarding both efficacy and safety., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Janus kinase [JAK] inhibitors have shown efficacy in ulcerative colitis [UC]. We studied the dose-response, efficacy, and safety of peficitinib, an oral JAK inhibitor, in patients with moderate-to-severe UC., Methods: In this Phase 2b, dose-ranging trial, we evaluated peficitinib at 25 mg once daily [o.d.], 75 mg o.d., 150 mg o.d., and 75 mg twice daily versus placebo for efficacy and safety in 219 patients with moderate-to-severe UC. The primary outcome was peficitinib dose-response at Week 8, with response assessed using Mayo score change from baseline. Secondary endpoints were clinical response, clinical remission, mucosal healing, change from baseline in Inflammatory Bowel Disease Questionnaire [IBDQ], and normalisation of inflammatory biomarkers at Week 8; other secondary endpoints were treatment response through Week 16 and through Week 32 for patients in clinical response at Week 8. Safety was assessed through Week 36 or 4 weeks after the last dose., Results: A statistically significant peficitinib dose-response was not demonstrated at Week 8, although a numerically greater proportion of patients receiving peficitinib ≥75 mg o.d. achieved clinical response, remission, and mucosal healing at Week 8, supported by IBDQ improvement and inflammatory biomarker normalisation. Treatment-emergent adverse event [TEAE] rates reported through Week 8 and the final safety visit were higher in the combined peficitinib group than in the placebo group; patients receiving doses of ≥75 mg o.d. peficitinib reported TEAEs more frequently., Conclusions: No dose-response in patients with moderate-to-severe UC was demonstrated with peficitinib, but evidence of efficacy was suggested at doses ≥75 mg o.d. The safety profile of peficitinib was consistent with current information. ClinicalTrials.gov NCT01959282.

Background and Aims: Safety and efficacy of budesonide multimatrix, an oral extended-release second-generation corticosteroid designed for targeted delivery throughout the colon, were examined for induction of remission in patients with mild to moderate ulcerative colitis refractory to baseline mesalamine therapy., Methods: A randomised, double-blind, placebo-controlled, multicentre trial evaluated efficacy and safety of budesonide multimatrix for induction of remission [ulcerative colitis disease activity index score ≥ 4 and ≤ 10] in 510 adults randomised to once-daily oral budesonide multimatrix 9 mg or placebo for 8 weeks. Patients continued baseline treatment with oral mesalamine ≥ 2.4 g/day., Results: Combined clinical and endoscopic remission at Week 8 was achieved by 13.0% and 7.5% of patients receiving budesonide multimatrix [n = 230] or placebo [n = 228], respectively, in the modified intention-to-treat population [p = 0.049]. Clinical remission [ulcerative colitis disease activity index rectal bleeding and stool frequency subscale scores of 0] was similar in both groups [p = 0.70]. More patients receiving budesonide multimatrix vs placebo achieved endoscopic remission [ulcerative colitis disease activity index mucosal appearance subscale score of 0; 20.0% vs 12.3%; p = 0.02] and histological healing [27.0% vs 17.5%; p = 0.02]. Adverse event rates were similar [budesonide multimatrix, 31.8%; placebo, 27.1%]. Mean morning cortisol concentrations decreased at Weeks 2, 4, and 8 with budesonide multimatrix but remained within the normal range., Conclusion: Budesonide multimatrix was safe and efficacious for inducing clinical and endoscopic remission for mild to moderate ulcerative colitis refractory to oral mesalamine therapy., (Copyright © 2017 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Goals: To evaluate the efficacy and safety of mesalamine granules 1.5 g once daily for maintenance of ulcerative colitis (UC) remission., Background: Mesalamine is a first-line treatment for induction and maintenance of UC remission., Study: A phase 3, randomized, double-blind, placebo-controlled trial of patients with a history of mild to moderate UC, currently in remission, who received mesalamine granules once daily for 6 months. The primary efficacy endpoint was percentage of patients maintaining UC remission at 6 months., Results: A significantly greater percentage of patients receiving mesalamine granules versus placebo were in remission at 6 months (79.9% vs. 66.7%; P=0.03). A greater percentage of patients receiving mesalamine granules maintained a revised Sutherland Disease Activity Index (SDAI)≤2 with no individual component of revised SDAI>1 and rectal bleeding=0 at 6 months (72.0% vs. 58.1%; P=0.04). No significant differences between groups were observed for change from baseline to 6 months for total SDAI score or its components (ie, stool frequency, rectal bleeding, mucosal appearance, physician's rating of disease). Mesalamine granules treatment resulted in a significantly longer remission duration versus placebo (P=0.02) and decreased patients' risk of relapse by 43% (hazard ratio=0.57; 95% confidence interval, 0.35-0.93; P=0.02). Mesalamine granules were well tolerated, and adverse events related to hepatic, renal, and pancreatic function-potential concerns with long-term treatment-occurred at a rate similar to placebo., Conclusions: Once-daily mesalamine granules are efficacious and safe for the maintenance of UC remission.

Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder in which patients cycle between active disease and remission. Budesonide multi-matrix (MMX) is an oral second-generation corticosteroid designed to deliver active drug throughout the colon. In pharmacokinetic studies, the mean relative absorption of budesonide in the region between the ascending colon and the descending/sigmoid colon was 95.9 %. In 2 identically designed, phase 3 studies (CORE I and II), budesonide MMX 9 mg once daily was efficacious and well tolerated for induction of remission of mild to moderate UC. Clinical and endoscopic remission rates were 17.9 % (CORE I) and 17.4 % (CORE II) for budesonide MMX 9 mg compared with 7.4 and 4.5 %, respectively, with placebo (p < 0.05, budesonide MMX 9 mg vs. placebo in both studies), 12.1 % with mesalamine 2.4 g, and 12.6 % with budesonide controlled ileal release capsules 9 mg. A 12-month maintenance therapy study suggested that budesonide MMX 6 mg may prolong time to clinical relapse: Median time was >1 year with budesonide MMX 6 mg versus 181 days (p = 0.02) with placebo; however, further studies are needed. In the CORE studies, budesonide MMX exhibited a favorable safety profile; the majority of adverse events were mild or moderate in intensity, and serious adverse events were uncommon. Furthermore, rates of potential glucocorticoid-related adverse events were comparable across treatment groups. The long-term (12-month) safety of budesonide MMX appears to be comparable with placebo. Data support budesonide MMX in the management algorithm of UC.

Background: Patients with ulcerative colitis (UC) who achieve remission with corticosteroids often relapse after tapering or discontinuation; alternative treatments limiting steroid exposure and UC relapse would be beneficial. It remains uncertain whether patients with corticosteroid-induced remission experience benefit with mesalamine granules (MG), a locally acting aminosalicylate extended-release capsule formulation for maintenance of UC remission in adults., Aims: Efficacy and safety of MG 1.5 g once daily was evaluated in patients with UC in corticosteroid-induced remission., Methods: Data from patients with previous corticosteroid use to achieve baseline UC remission were analyzed from two 6-month randomized, double-blind, placebo-controlled trials and a 24-month open-label extension (OLE). Six-month relapse-free rates were assessed using the revised Sutherland Disease Activity Index. UC-related adverse events (AEs) were recorded during the 30 months., Results: Included were 158 steroid-treated patients in UC remission (MG, n = 105; placebo, n = 53) and 74/105 MG-treated patients who continued MG in the OLE. A significantly larger percentage of patients remained relapse-free at 6 months with MG (77.1 %) versus placebo (54.7 %; P = 0.006), with a 55 % reduction in relapse risk (hazard ratio [HR] 0.45; 95 % CI 0.25-0.79). There was a similar (49.2 %) reduction in risk of UC-related AEs at 6 months (HR 0.51; 95 % CI 0.31-0.84; P = 0.009) that was sustained during the OLE., Conclusions: MG 1.5 g once daily administered for maintenance of corticosteroid-induced remission was associated with low risk of relapse and UC-related AEs. CLINICALTRIALS.GOV: NCT00744016, NCT00767728, and NCT00326209.

Objectives: A capsule formulation of mesalamine granules (MG) was developed for once-daily dosing and better compliance. The study aim was to evaluate MG efficacy and tolerability in maintaining ulcerative colitis (UC) remission., Methods: Pooled analysis of 2 identical phase 3, randomized, double-blind trials of once-daily MG 1.5 g or placebo for up to 6 months. The primary endpoint was percentage of patients remaining relapse-free at month 6 versus placebo. Relapse was defined as revised Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, UC flare, or UC-related adverse event (AE)., Results: Data were pooled for patients receiving MG (n = 373) and placebo (n = 189). Significantly more patients were relapse-free at 6 months with MG (79.4%) than placebo (62.4%; P < 0.001) and across subgroups based on select demographic and baseline characteristics (P < 0.05). Secondary outcome measures including rectal bleeding, physician rating of disease activity, stool frequency, total SDAI score, and relapse-free duration favored MG (P < 0.01). Common AEs with MG and placebo, respectively, were headache (10.9% and 7.6%), diarrhea (7.9% and 7.0%), and abdominal pain (6.3% and 6.5%)., Conclusion: Once-daily MG was more efficacious than and as well tolerated as placebo in maintaining UC remission. ClinicalTrials.gov identifiers: NCT00744016 and NCT00767728.

Background: The Crohn's Disease Activity Index (CDAI) and Mayo score for ulcerative colitis (UC) require symptom recall and/or use of a symptom diary. We examined patients' abilities to recall their symptoms and the day-to-day variability of symptoms., Methods: Patients with UC or CD completed a questionnaire including items from the short CDAI (sCDAI) and the 6-point Mayo score. Patients were randomized to receive a follow-up questionnaire testing recall of the bowel symptom items between 1 and 7 days later. In a second study, patients completed a 7-day electronic diary recording their symptoms. sCDAI and 6-point Mayo scores were computed. Analyses estimated daily variability in the indices and misclassification rates when using fewer than 7 days of data., Results: 100%, 82%, and 90% of CD participants recalled the same disease activity status (i.e., active versus remission) as reported on the initial survey when the follow-up questionnaire was administered 1 to 2, 3 to 5, and 6 to 8 days later, respectively. Compared with using 7 days of data, when using only day 7 data, 3.7% of patients with CD were misclassified as active or inactive. Disease activity was misclassified in 2.8%, 4.9%, and 3.3% of patients by using the last 2, 3, or 4 days, respectively. Results were similar for patients with UC., Conclusions: Patients with CD and UC demonstrated good recall of bowel symptoms for up to 8 days. Additionally, bowel symptoms have relatively little variability within a 7-day period allowing for accurate computation of the sCDAI and 6-point Mayo score using 1 to 3 days of data.

Background and Aims: Cumulative safety and tolerability of budesonide MMX, a once-daily oral corticosteroid for inducing mild to moderate ulcerative colitis remission, was examined., Methods: Data from three randomized, double-blind, placebo-controlled, phase II or III studies [budesonide MMX 9 mg, 6 mg, or 3mg for 8 weeks]; one phase II study [randomisation to budesonide MMX 9 mg or placebo for 4 weeks, then open-label budesonide MMX 9 mg for 4 weeks]; and one open-label study [budesonide MMX 9 mg for 8 weeks] were pooled., Results: Patients randomised to budesonide MMX 9 mg [n = 288], 6 mg [n = 254], or placebo [n = 293] had similar rates of adverse events [AEs] [27.1%, 24.8%, and 23.9%, respectively] and serious AEs [2.4%, 2.0%, and 2.7%, respectively]; treatment-related AEs and serious AEs were reported by 11.8% and 13.5%, and 5.9% and 2.2%, respectively, of patients receiving budesonide MMX 3mg [n = 17] or open-label budesonide MMX 9 mg [n = 89]. Mean morning plasma cortisol concentrations were normal from baseline to final visit across randomised groups; in patients receiving open-label budesonide, mean cortisol concentration was 129.9 nmol/l after 4 weeks, returning to normal concentrations at final visit. Budesonide MMX was not associated with an overall increased risk for glucocorticoid-related adverse effects., Conclusions: Budesonide MMX 9 mg was associated with normal mean cortisol concentrations at final visit and an AE incidence comparable to placebo. Overall, budesonide MMX was safe and well tolerated for inducing remission of patients with mild to moderate ulcerative colitis., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: To determine whether clinical information influences endoscopic scoring by central readers using the Ulcerative Colitis Endoscopic Index of Severity [UCEIS; comprising 'vascular pattern', 'bleeding', 'erosions and ulcers']., Methods: Forty central readers performed 28 evaluations, including 2 repeats, from a library of 44 video sigmoidoscopies stratified by Mayo Clinic Score. Following training, readers were randomised to scoring with ['unblinded', n = 20, including 4 control videos with misleading information] or without ['blinded', n 20] clinical information. A total of 21 virtual Central Reader Groups [CRGs], of three blinded readers, were created. Agreement criteria were pre-specified. Kappa [κ] statistics quantified intra- and inter-reader variability., Results: Mean UCEIS scores did not differ between blinded and unblinded readers for any of the 40 main videos. UCEIS standard deviations [SD] were similar [median blinded 0.94, unblinded 0.93; p = 0.97]. Correlation between UCEIS and visual analogue scale [VAS] assessment of overall severity was high [r blinded = 0.90, unblinded = 0.93; p = 0.02]. Scores for control videos were similar [UCEIS: p ≥ 0.55; VAS: p ≥ 0.07]. Intra- [κ 0.47-0.74] and inter-reader [κ 0.40-0.53] variability for items and full UCEIS was 'moderate'-to-'substantial', with no significant differences except for intra-reader variability for erosions and ulcers [κ blinded: 0.47 vs unblinded: 0.74; p 0.047]. The SD of CRGs was lower than for individual central readers [0.54 vs 0.95; p < 0.001]. Correlation between blinded UCEIS and patient-reported symptoms was high [stool frequency: 0.76; rectal bleeding: 0.82; both: 0.81]., Conclusions: The UCEIS is minimally affected by knowledge of clinical details, strongly correlates with patient-reported symptoms, and is a suitable instrument for trials. CRGs performed better than individuals., (© European Crohn’s and Colitis Organisation 2015.)

Objectives: There are limited data on the risk of non-melanoma skin cancer (NMSC) and melanoma skin cancer (MSC) among thiopurine-treated patients with ulcerative colitis (UC). Our aim was to investigate the risk while on, by cumulative years, and after stopping thiopurine therapy., Methods: Nationwide data were obtained from the Veterans Affairs (VA) health-care system during 2001-2011. We performed a retrospective cohort study evaluating patients with UC. Cox regression was used to investigate the association between thiopurines use and time to NMSC while adjusting for demographics, ultraviolet radiation exposure, and VA visiting frequency. A matched nested case-control study was conducted to investigate the association between thiopurine use and MSC., Results: We included 14,527 patients with UC in the analysis, with a median follow-up of 8.1 years. A total of 3,346 (23%) patients used thiopurines for a median duration of 1.6 years. We identified 421 NMSC and 45 MSC cases. The adjusted hazard ratios of developing NMSC while on and after stopping thiopurines were 2.1 (P<0.0001) and 0.7 (P=0.07), respectively, as compared with unexposed patients. The incidence rate of NMSC among those who never used thiopurines was 3.7 compared with 5.8, 7.9, 8.3, 7.8, and 13.6 per 1,000 person-years for the 1st, 2nd, 3th, 4th, and 5th year of thiopurine use, respectively. No statistically significant association was observed between thiopurine use and MSC, odds ratio 0.8 (P=0.6)., Conclusions: In this predominantly white male nationwide cohort, there was a twofold increase in the risk of NMSC while on thiopurines. The incidence rate of NMSC significantly increased with subsequent years of cumulative exposure to thiopurines. Stopping thiopurines reduced the risk of NMSC to pre-exposure levels irrespective of the prior exposure duration.

Background: Ulcerative colitis (UC), a chronic, relapsing, and remitting inflammatory bowel disease, requires long-term treatment to maintain remission. In this study, the long-term safety and tolerability of mesalamine granules (MG) therapy was evaluated in the maintenance of UC remission. Previous prospective studies evaluating different oral mesalamine formulations have not exceeded a duration of 14 months., Methods: A phase 3, multicenter, 24-month, open-label extension study evaluating MG 1.5 g once daily in patients who achieved previous remission from mild to moderate UC was performed. Eligible patients had successfully participated in 1 of 2 previous 6-month double-blind, placebo-controlled trials or were new patients in remission. Safety assessments included monitoring of adverse events (AEs) and clinical laboratory tests. Risk of UC recurrence was assessed by the occurrence of UC-related AEs., Results: Of the 393 patients enrolled (280 from the double-blind studies; 113 new patients), 388 were included in the safety population. The most common AEs included nasopharyngitis (13.9%), headache (11.6%), and diarrhea (10.8%), and the incidence of these events was generally lower in the MG group versus historical placebo group from the double-blind studies. Pancreatic, renal, and hepatic AEs occurred in 23 patients (5.9%). The risk of UC-related AEs was low and was maintained for 24 months during the open-label study., Conclusions: Once-daily MG has a favorable safety profile for the maintenance of remission for up to 2 years in patients with UC.

Purpose of Review: The increased understanding of the molecular mechanisms that are responsible for inflammatory bowel disease (IBD) has led to a wide range of potential therapeutic targets for this condition. Physicians treating individuals with Crohn's disease and ulcerative colitis have a growing armamentarium of options to choose from in managing these patients. This article aims to summarize the relevant literature in the area of emerging therapy in IBD., Recent Findings: The widespread use of antitumor necrosis factor medications brought a landmark change in the treatment of IBD. More recently, several drugs have been shown to provide benefit in IBD in phase III studies by blocking other antiinflammatory pathways. The most likely new medications that will be available include vedolizumab for ulcerative colitis and ustekinumab for Crohn's disease, which target cellular adhesion and inflammatory cell signaling, respectively. Other promising drugs focus on blockade of Janus kinase, inhibition of various chemokines, and biologic therapy such as hematopoietic stem cell transplants and mesenchymal cell infusions., Summary: The growing understanding of the pathogenesis of IBD has led to new molecular targets for therapy. Over the next decade, the number of treatments available will grow, targeting cellular adhesion, protein regulation, inflammatory signal pathways, and immune tolerance.

Purpose of Review: Ulcerative colitis is a chronic inflammatory disease of the colon of unknown cause that is characterized by alternating intervals of active and inactive disease in 80-90% of patients. The primary goal of treatment is to induce and maintain remission using therapy tailored to the individual patient. The purpose of this review was to describe the management of ulcerative colitis with emphasis on the use of anti-tumor necrosis factor (TNF) agents., Recent Findings: Recent research has shown that new anti-TNF agents, adalimumab (ADA) and golimumab, are effective in induction of remission and maintenance of remission in patients with extensive ulcerative colitis. In a recent study, infliximab was found to have comparable efficacy to cyclosporine in treatment of acute severe refractory to corticosteroids ulcerative colitis., Summary: Anti-TNF therapy should be initiated in patients with acute severe refractory to corticosteroids ulcerative colitis and in patients with moderate-to-severe ulcerative colitis who are not responsive to conventional treatment with aminosalicylates, corticosteroids and immune modulators. Alternatives to infliximab are ADA and golimumab. Future research is needed to further assess the long-term efficacy and safety of ADA and golimumab in ulcerative colitis.

Background & Aims: We studied the reliability of the previously described Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and validated it with an independent cohort of investigators., Methods: We created a new library of 57 videos of flexible sigmoidoscopy and stratified them based on disease severity. Twenty-five investigators were each randomly assigned to assess 28 videos (which included 4 duplicates to assess intraobserver reliability). Investigators were blinded to clinical details except for 2 of 4 duplicated videos (to assess the impact of knowledge of symptoms on assessment). Three descriptors ("vascular pattern", "bleeding", and "erosions and ulcers") comprising the UCEIS were scored with a visual analogue scale (VAS) to assess overall severity. Intrainvestigator and interinvestigator agreement was characterized by κ statistical analysis; reliability ratios were used to compare VAS and UCEIS scores., Results: There was a high level of correlation between UCEIS scores and overall assessment of severity (correlation coefficient, 0.93). Internal consistency (Cronbach α analysis) was 0.86. Intrainvestigator and interinvestigator reliability ratios for UCEIS scores were 0.96 and 0.88, respectively. Intrainvestigator agreement in determination of the UCEIS score was good (κ = 0.72), with individual descriptors ranging from a κ of 0.47 (for bleeding) to 0.87 (for vascular pattern). Interinvestigator agreement in determination of UCEIS scores was moderate (κ = 0.50), with descriptors ranging from a κ of 0.48 (for bleeding) to 0.54 (for vascular pattern). Intrainvestigator variability in determining UCEIS scores did not change appreciably when a video was presented with clinical details., Conclusions: The UCEIS and its components show satisfactory intrainvestigator and interinvestigator reliability. Among investigators, the UCEIS accounted for a median of 86% of the variability in evaluation of overall severity on the VAS when assessing the endoscopic severity of UC and was unaffected by knowledge of clinical details., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: There is controversy over whether the treatment of patients with ulcerative colitis (UC) with thiopurines increases their risk of lymphoma. We evaluated the risk of lymphoma (ongoing, residual, and per year of therapy) among thiopurine-treated patients with UC., Methods: We obtained nationwide data from the Veterans Affairs (VA) health care system from 2001 to 2011. We performed a retrospective cohort study, analyzing data on 36,891 patients from their date of diagnosis of UC in the VA health care system to a diagnosis of lymphoma or October 1, 2011 (subjects followed up for a median of 6.7 years). Thiopurine exposure was assessed using the VA pharmacy database. Patients who developed lymphoma were identified based on ICD-9 codes and confirmed by manual chart review., Results: In total, 4734 patients with UC (13%) were treated with thiopurines for a median of 1 year. Lymphoma developed in 119 patients who had not been treated with thiopurines, 18 who were treated with thiopurines, and 5 who had discontinued treatment with thiopurines. The incidence rates of lymphoma were 0.60 per 1000 person-years among patients who had not been treated with thiopurines, 2.31 among patients who were treated with thiopurines, and 0.28 among patients who had discontinued treatment with thiopurines. The incidence rates of lymphoma during the first year, second year, third year, fourth year, and >4 years of thiopurine therapy were 0.9, 1.6, 1.6, 5, and 8.9 per 1000 person-years, respectively. The age-, sex-, and race-adjusted hazard ratios of developing lymphoma were 4.2 (95% confidence interval, 2.5-6.8; P < .0001) while being treated with thiopurines and 0.5 (95% confidence interval, 0.2-1.3; P = .17) after discontinuing treatment with thiopurines compared with patients who had not been treated with thiopurines., Conclusions: Based on a retrospective, nationwide cohort study, patients with UC have a 4-fold increase in risk of lymphoma while being treated with thiopurines compared with patients who have not been treated with thiopurines. The risk increases gradually for successive years of therapy. Discontinuing thiopurine therapy reduces the risk of lymphoma., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim: To formally study age of diagnosis of papillary thyroid cancer (PTC) in inflammatory bowel disease (IBD) patients and evaluate the prevalence of PTC in IBD patients compared to a control population., Methods: We were interested in testing the hypothesis that patients with IBD are more likely to be diagnosed with PTC than a control population. A retrospective cohort analysis was performed using the University of Pennsylvania Health System's electronic database. Outpatients from 1998-2009 were included in the search, and patients in the cohort were selected based on ICD-9 codes. Inclusion criteria included the diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) and the concurrent diagnosis of thyroid cancer in comparison to a control population. Using these methods 912 patients with CD and 1774 with UC were compared to 1638 diverticulitis and 19 447 asthma controls. Statistics were performed using corrected chi-square analysis. The primary outcome for this study was the diagnosis of PTC. Approval to conduct this study was obtained by the Institutional Review Board at the University of Pennsylvania., Results: The mean age was 47.5 years (range: 18-102 years) and 66% patients were female. An analysis of variance model was used to compare the age of PTC diagnosis between the CD, UC, asthma and diverticulitis groups, and a statistically significant difference in age at PTC diagnosis was noted across all groups (F = 6.35, df = 3, P = 0.0006). The age of PTC diagnosis in CD patients was statistically significantly lower than UC, asthma, and diverticulitis patients (average PTC diagnosis age for CD 25, UC 49, asthma 45, diverticulitis 63). After covarying for sex and age in 2009, the difference in age at PTC diagnosis remained statistically significant (F = 4.13, df = 3, P = 0.0089). A total of 86 patients were diagnosed with PTC. Nine patients (0.5%) with UC were diagnosed with PTC. Patients with UC were not shown to be more likely to develop PTC [odds ratio (OR): 1.544, 95%CI 0.767-3.108] compared to asthma controls. Four patients (0.4%) with CD were diagnosed with PTC. Patients with CD were not shown to be more likely to develop PTC (OR: 1.334, 95%CI 0.485-3.672) compared to a control population with asthma. Nine patients (0.5%) with a history of diverticulitis were diagnosed with PTC. Patients with diverticulitis were not shown to be more likely to develop PTC (OR: 1.673, 95%CI 0.831-3.368) compared to asthma controls. Patients with CD or UC were not less likely to develop PTC compared to those with diverticulitis (CD OR: 0.80, 95%CI 0.25-2.60; UC OR: 0.92, 95%CI 0.37-2.33). None of the patients used immunosuppressant medications prior to the diagnosis of PTC (azathioprine, 6-mercaptopurine, and methotrexate)., Conclusion: There is a significant difference in age of diagnosis of PTC in patients with CD compared to patients with UC and the control populations studied.

Objectives: The objective of this study was to analyze the safety of long-term infliximab treatment, with/without concomitant immunomodulators, across Crohn's disease (CD) and ulcerative colitis (UC) clinical trials., Methods: To maximize sample size, we pooled primary safety data across 10 CD or UC trials, including five randomized, controlled trials contributing data from patients who received intravenous infliximab 5 or 10 mg/kg (n=1,713; ±azathioprine) or placebo (n=406; ±azathioprine). Pooled incidences and 95% confidence intervals (CIs) were determined for mortality, infection, and malignancy. Standardized incidence ratios and 95% CIs were also determined for malignancies using the Surveillance, Epidemiology, and End Results database., Results: We observed no increase in infections, serious infections, or malignancy with infliximab vs. placebo in these patients with inflammatory bowel disease (IBD). In patients with UC, but not CD, immunomodulator treatment (vs. treatment without immunomodulator) yielded a higher incidence (95% CI) of infections (120.07 (110.66, 130.08)/100 patient-years (pt-yrs) vs. 92.47 (84.54, 100.94)/100 pt-yrs). Among placebo-treated patients with CD, but not UC, those with immunomodulator use demonstrated a higher incidence (95% CI) of malignancy vs. no immunomodulator treatment (1.84 (0.22, 6.66)/100 pt-yrs vs. 0.00 (0.00, 0.00)/100 pt-yrs). Mortality and infection-related mortality appeared unaffected by infliximab or immunomodulator treatment., Conclusions: Infliximab treatment of IBD did not appear to affect incidences of infection, mortality, or malignancy. Relative to patients with no immunomodulator use, immunomodulator-treated UC patients demonstrated a higher incidence of infection and immunomodulator-plus-placebo-treated CD patients demonstrated a higher incidence of malignancy.

Many clinical factors predict the aggressive course of CD. Younger age at initial diagnosis, the presence of perianal lesions, ileal involvement, smoking, and the need for therapy with corticosteroids are the major predictors of disabling disease or change of behavior to a more aggressive disease. On the other hand, treatment with azathioprine and biologic agents and colonic localization of disease are the major factors that are predictive of less aggressive CD course. The problem we face with determining the factors that increase the risk of disabling disease is that there is no standardized and consistent definition of disabling or aggressive disease. Only two studies analyzed predictors using the same definition of aggressive disease. Only Beaugerie and colleagues developed the score predictive of disabling disease based on three independent factors associated with disabling course that were present at the time of initial diagnosis of CD (requirement of corticosteroids, age less than 40 years, and presence of perianal disease). This score ranged from 0 to 3 points based on the presence of given parameters. The positive predictive value was 0.91 and 0.93 in patients having two or three risk factors, 0.61 for no factors present, and 0.67 for one factor present. In order to determine factors predictive of disabling CD there is a need to establish consistent definition of disabling disease with subsequent future studies on large group of patients to validate such definition and determine factors that may predict the aggressive course.

Background: Variability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC)., Objective: To evaluate variation in the overall endoscopic assessment of severity, the intra- and interindividual variation of descriptive terms and to create an Ulcerative Colitis Endoscopic Index of Severity which could be validated., Design: A two-phase study used a library of 670 video sigmoidoscopies from patients with Mayo Clinic scores 0-11, supplemented by 10 videos from five people without UC and five hospitalised patients with acute severe UC. In phase 1, each of 10 investigators viewed 16/24 videos to assess agreement on the Baron score with a central reader and agreed definitions of 10 endoscopic descriptors. In phase 2, each of 30 different investigators rated 25/60 different videos for the descriptors and assessed overall severity on a 0-100 visual analogue scale. κ Statistics tested inter- and intraobserver variability for each descriptor. A general linear mixed regression model based on logit link and β distribution of variance was used to predict overall endoscopic severity from descriptors., Results: There was 76% agreement for 'severe', but 27% agreement for 'normal' appearances between phase I investigators and the central reader. In phase 2, weighted κ values ranged from 0.34 to 0.65 and 0.30 to 0.45 within and between observers for the 10 descriptors. The final model incorporated vascular pattern, (normal/patchy/complete obliteration) bleeding (none/mucosal/luminal mild/luminal moderate or severe), erosions and ulcers (none/erosions/superficial/deep), each with precise definitions, which explained 90% of the variance (pR(2), Akaike Information Criterion) in the overall assessment of endoscopic severity, predictions varying from 4 to 93 on a 100-point scale (from normal to worst endoscopic severity)., Conclusion: The Ulcerative Colitis Endoscopic Index of Severity accurately predicts overall assessment of endoscopic severity of UC. Validity and responsiveness need further testing before it can be applied as an outcome measure in clinical trials or clinical practice.

Background: The aim was to evaluate long-term efficacy, quality of life, and safety in ulcerative colitis patients who received infliximab during the ACT-1 and -2 extension studies., Methods: Adults with moderate-to-severely active ulcerative colitis in the 54-week ACT-1 and 30-week ACT-2 studies who achieved benefit from infliximab were eligible to participate in extension studies and receive up to 3 additional years of therapy. Patients received randomized study medication until all sites were unblinded; placebo-treated patients were discontinued. Patients receiving 5 or 10 mg/kg infliximab continued to receive open-label infliximab every 8 weeks. Patients receiving infliximab 10 mg/kg could decrease to 5 mg/kg; patients receiving infliximab 5 mg/kg could increase to 10 mg/kg if response was lost., Results: A total of 229 of 484 infliximab-treated patients from the ACT-1 and ACT-2 main studies entered the long-term extensions. Overall, 70 (30.6%) patients discontinued infliximab infusions for adverse events (24 [10.5%]), lack of efficacy (11 [4.8%]), required a colectomy (1 [0.4%]), or for other reasons (34 [14.8%]). Proportions of patients whose Physician's Global Assessment scores were indicative of no or mild disease (score = 0 or 1) were maintained during the extension studies; 76.5% at Extension week 0 and ranged between 90.0% and 94.3% through Extension week 152. Improvement in Inflammatory Bowel Disease Questionnaire scores observed in the main studies was maintained. During the long-term extension, the infliximab safety profile was consistent with that of the main studies; no new or unexpected safety signals were observed., Conclusions: Long-term treatment with infliximab for up to 3 additional years was effective and well tolerated., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Background & Aims: In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome., Methods: Patients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0-3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild)., Results: Infliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P=.0004). This trend was not observed among patients given placebo (P=.47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P<.0001, infliximab; P<.01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission., Conclusions: The degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Patients with chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis have an increased risk of myocardial infarction (MI). Studies of the risk of MI among patients with inflammatory bowel disease have provided inconsistent results. We aimed to determine the risk of first-time acute MI in patients with ulcerative colitis (UC) or Crohn's disease (CD) compared with patients from general practice., Methods: We conducted 2 retrospective cohort studies using the General Practice Research Database. A total of 15,498 UC patients were matched to 144,605 general practice patients (for age, sex, year of enrollment in the General Practice Research Database, and general practice of attendance) and were followed up for a mean of 4.7 years; 9829 CD patients were matched to 92,987 patients from general practice and followed up for a mean of 4.5 years. Univariable and multivariable Cox regression analyses were adjusted for age, sex, history of hypertension, diabetes mellitus, hypercholesterolemia, smoking status, body mass index, and aspirin use for each cohort., Results: Patients with UC had a significantly increased risk of first-time acute MI compared with patients from general practice in unadjusted, but not adjusted, analysis (adjusted hazard ratio, 1.11; 95% confidence interval, 0.98-1.27). Patients with CD did not have an increased risk of MI in either unadjusted or adjusted analyses (adjusted hazard ratio, 1.09; 95% confidence interval, 0.89-1.34)., Conclusions: Unlike some other chronic inflammatory diseases, inflammatory bowel disease is not associated with an increased risk of MI., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Mesalamine has been the first-line of therapy in patients with inflammatory bowel disease (IBD) since the 1960s. This article serves as a review of the different 5-aminosalicylic acid compounds, release formulations, use and dosing in the treatment of IBD, in particular ulcerative colitis., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Treatment of patients with ulcerative colitis (UC) has traditionally focused on improving symptoms, with the main objective of inducing and maintaining symptomatic remission. However, new evidence suggests that concentrating exclusively on clinical outcome measures may not be adequate to achieve long-term treatment success. Indeed, physicians should also be assessing the reduction of endoscopic activity, with the intention of achieving complete mucosal healing (defined as the absence of all mucosal ulceration, both microscopic and macroscopic, providing a sigmoidoscopy score of 0, as assessed on the Ulcerative Colitis Disease Activity Index). As a consequence of the customary reliance on symptomatic outcome measures, relatively few clinical trials have used mucosal healing or a composite including mucosal healing as a primary endpoint. This situation may soon change as new guidelines recommend the incorporation of mucosal healing into the primary endpoint of all new clinical trials in patients with UC. These recommendations are derived, in part, from data that have illustrated a correlation between mucosal healing and several important factors including long-term remission rates, disease-related complications (e.g., risk of colorectal cancer), healthcare utilization (e.g., need for colectomy), and patient quality of life. We already have drugs available to us that can effectively induce and maintain complete mucosal healing over long periods of time. This review evaluates the effect of medical therapy on mucosal healing in patients with UC and explores the importance of this outcome measure, both from the patient's perspective and clinical trial experience. Inflamm Bowel Dis 2009.

Background & Aims: The efficacy of infliximab for treating patients with ulcerative colitis has been established., Methods: The Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 randomized, double-blind, placebo-controlled studies evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis. Overall, 728 patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2). Colectomy, hospitalization, and surgery/procedure data through 54 weeks after the first infusion were obtained from ACT-1, ACT-2, and associated data sources. In the prespecified analysis, all data were combined to ascertain time to colectomy. Kaplan-Meier product-limit method was used to estimate the cumulative incidence of colectomy, and log-rank test was used to compare the combined infliximab group and placebo., Results: Eighty-seven percent (630 of 728) of patients had complete colectomy follow-up; 13% (98 of 728) of patients had a median follow-up of 6.2 months. The cumulative incidence of colectomy through 54 weeks was 10% for infliximab and 17% for placebo (P = .02), yielding an absolute risk reduction of 7%. Compared with placebo, fewer ulcerative colitis-related hospitalizations and surgeries/procedures per 100 patient-years of treatment occurred with infliximab therapy: 40 vs 20 (P = .003) and 34 vs 21 (P = .03), respectively. Serious adverse events occurring in infliximab-treated patients included serious infections, tuberculosis, histoplasmosis, listeriosis, and malignancy., Conclusions: Patients with moderately to severely active ulcerative colitis treated with infliximab were less likely to undergo colectomy through 54 weeks than those receiving placebo.

Background: Many patients with ulcerative colitis (UC) respond to mesalamine therapy within 8 weeks. Those not achieving remission after 8 weeks are often treated with steroids or other immunosuppressive therapies. This study aimed to determine the effect of 8 weeks' high-dose MMX mesalamine extension therapy in patients with active, mild-to-moderate UC who had previously failed to achieve complete remission in 2 phase III, double-blind, placebo-controlled studies of MMX mesalamine (SPD476-301 and -302)., Methods: Patients with active, mild-to-moderate UC who did not achieve clinical and endoscopic remission after or=1 point reduction from baseline in sigmoidoscopy score., Results: Overall, 304 patients who entered this acute extension study were evaluated; 59.5% achieved remission at week 8. Remission rates were similar irrespective of prior treatment in the initial acute phase III studies., Conclusions: Most patients with mild-to-moderate UC who fail to achieve remission with up to 8 weeks' initial mesalamine therapy can achieve clinical and endoscopic remission following a further 8 weeks' treatment with high-dose MMX mesalamine therapy, thereby avoiding step-up therapy.

Ulcerative colitis is an idiopathic chronic inflammatory disease of the colon characterized by symptoms of bloody diarrhea and abdominal pain. Although conventional aminosalicylates have been the foundation of treatment of mild to moderate ulcerative colitis for both the induction and maintenance of remission, they are limited in a number of ways, such as which formulation and what dose are optimal, as well as the high pill burden, which often leads to low compliance with these medications. Multi-Matrix System (MMX) mesalamine (SPD476) is a promising new aminosalicylate formulation; it seems to have solved some of the problems of conventional aminosalicylates, as it is effective as a once-daily treatment in high doses and induces both clinical remission and endoscopic mucosal healing. This review article summarizes the data on the use of both conventional aminosalicylates and MMX mesalamine in the treatment of ulcerative colitis., (Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.)

Recent evidence suggests that there is a link between increased colonic inflammation and risk of colorectal cancer, stressing the importance of preventing relapse. The risk of relapse is associated with several factors, of which the foremost is patient nonadherence to prescribed medical therapy. Nonadherence may be affected by such factors as complicated dosing regimens, forgetfulness, male sex, and treatment delivery methods. Mesalamine is the standard, first-line therapy and the treatment of choice for inducing and maintaining clinical and endoscopic remission of inflammation in patients with mild-to-moderate ulcerative colitis. Novel formulations of mesalamine and newly devised, high-dose regimens offer additional therapeutic options and may lead to improved treatment adherence, longer-lasting periods of remission, and enhanced patient well-being.

Background: The Mayo score and a noninvasive 9-point partial Mayo score are used as outcome measures for clinical trials assessing therapy for ulcerative colitis (UC). There are limited data assessing what defines a clinically relevant change in these indices. We sought to assess what constitutes a clinically meaningful change in these indices using data from a recently completed placebo-controlled clinical trial., Methods: In all, 105 patients were enrolled in a 12-week randomized, placebo-controlled trial assessing rosiglitazone for treatment of mild to moderate UC. We compared the change in the Mayo score, the partial Mayo score, and a 6-point score composed just of the stool frequency and bleeding components of the Mayo score to the patient's perception of disease activity at week 0 and week 12. Optimal cutpoints were calculated as the maximal product of sensitivity and specificity., Results: Each index was strongly correlated with the patient's rating of disease activity at week 12 (Spearman correlations 0.61-0.71, P < 0.0001 for all correlations). The maximal product of sensitivity and specificity to identify patient reported improvement of disease activity was achieved using cutpoints for change of 2.5 for the Mayo score (sensitivity 88%, specificity 80%), 2.5 for the partial Mayo score (sensitivity 88%, specificity 87%), and 1.5 for the 6-point score (sensitivity 88%, specificity 80%)., Conclusions: The partial Mayo score and the 6-point score composed solely of the stool frequency and bleeding components performed as well as the full Mayo score to identify patient perceived clinical response.

Mesalamine with MMX Multi Matrix System technology (hereafter referred to as MMX mesalamine) is an oral, high-strength (1.2 g/tablet), once-daily formulation of 5-aminosalicylic acid used for the treatment of ulcerative colitis. This new formulation has been designed to provide delayed and prolonged 5-aminosalicylic acid release throughout the colon. In recent clinical studies, MMX mesalamine (taken as a once-daily dose of 2.4 or 4.8 g) effectively induced clinical remission and mucosal healing versus placebo in patients with active, mild-to-moderate ulcerative colitis. Once remission was achieved, MMX mesalamine effectively maintained disease remission in the majority of patients for at least 12 months. In this paper, we comprehensively review the results of studies exploring the clinical pharmacology, efficacy and safety of MMX mesalamine in patients with ulcerative colitis, and examine the implications of these findings on clinical practice.

Background & Aims: Thiazolidinedione ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARgamma), widely used to treat type 2 diabetes mellitus, have been proposed as novel therapies for ulcerative colitis (UC)., Methods: This multicenter, randomized, double-blind, placebo-controlled clinical trial compared the efficacy of rosiglitazone (Avandia; GlaxoSmithKline, Philadelphia, PA) 4 mg orally twice daily vs placebo twice daily for 12 weeks in 105 patients with mild to moderately active UC. Disease activity was measured with the Mayo score. The primary end point was clinical response (>/=2-point reduction) at week 12. Clinical remission (Mayo score

Bowman-Birk inhibitor concentrate (BBIC), a soy extract with high protease inhibitor activity, is efficacious in the treatment of colitis in mice and has been used in numerous clinical trials. A randomized, double blind, placebo-controlled trial was performed to investigate the safety and possible benefits of BBIC in patients with active ulcerative colitis. The Sutherland Disease Activity Index (SDAI) was used to assess disease activity, response (Index decrease > or = 3), and remission (Index < or = 1 with no rectal bleeding) in patients receiving 12 weeks of therapy. The Index scores of patients receiving BBIC decreased more than those of the patients receiving placebo (P = 0.067). Beneficial trends were observed in the rates of remission (P = 0.082) and clinical response (P = 0.22). No severe adverse events were observed. This trial suggests a potential benefit over placebo for both achieving clinical response and induction of remission in patients with active ulcerative colitis without apparent toxicity.

Objective: Patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer. It was widely believed that dysplastic lesions are invisible on colonoscopy and can only be detected by random biopsies, as 95% of dysplastic lesions occur in flat colonic mucosa indistinct from surrounding tissue. The aim of this study was to determine whether dysplasia is visible during routine surveillance colonoscopy by evaluating only patients who had dysplasia without overt carcinoma., Material and Methods: The medical records, endoscopy and pathology databases were systematically reviewed between 1997 and 2004 at the University of Pennsylvania Health System. Patients with inflammatory bowel disease and dysplasia were identified and their medical charts reviewed., Results: Of the 113 patients with colonic dysplasia confirmed by pathology at our center, 102 (90%) had UC. Forty-nine of the 102 (48%) patients with UC underwent colonoscopic evaluation prior to dysplasia detection. This group was selected as our study cohort. Overall, 72 macroscopic abnormalities were detected at 49 colonoscopies, including 55 polypoid lesions, 12 areas of ulceration, 3 areas of nodularity, 1 irregular hemicircumferential lesion and 1 area of stricture. Overall, 58 dysplastic sites were detected; 51 were macroscopically visible (87.9%) and 7 were macroscopically invisible (12.1%)., Conclusions: Most of the dysplasia in UC is endoscopically visible, but further prospective evaluation of a large number of patients is needed to validate the current observations. Our findings have the potential to modify current recommendations for surveillance biopsies in UC if validated by prospective studies.

Objective: The management of high-grade dysplasia (HGD) in polypoid lesions in patients with ulcerative colitis (UC) is not well characterized. The purpose of this study was to characterize the clinical course of patients with HGD in adenoma-like dysplasia-associated lesion or masses (DALMs) in the absence of any synchronous flat dysplasia. We hypothesize that colectomy is not warranted in patients who undergo complete excision of adenoma-like DALMs with HGD in UC., Material and Methods: Pathology and clinical databases were systematically searched for the presence of dysplastic lesions in inflammatory bowel disease from 1997 to 2004. Patients with UC who had adenoma-like DALMs were identified, and a subset with HGD lesions was defined as our study cohort., Results: A total of 102 patients with UC were identified. Thirty of them (29%) had adenoma-like DALMs without synchronous flat dysplasia; 9 of these patients (30%) had HGD in these lesions. Thirty-two surveillance colonoscopies were performed in this cohort (mean 3.6 colonoscopies/patient). The patients were followed for a mean of 76.5 months (52-99 months). Three out of 9 patients (33%) had colectomy. None of the patients in this cohort was detected to have carcinoma in surveillance biopsies and/or in the resection specimens., Conclusions: Our data suggest that the presence of HGD in DALMs does not warrant colectomy. Continued close observation is suggested in this patient cohort after complete excision of polyps. Further prospective evaluation of this patient population is merited.

Background & Aims: Knowledge of the placebo outcomes and understanding specific study features that influence these outcomes is important for designing future clinical trials evaluating therapy of ulcerative colitis (UC). The aims of this study were to estimate the placebo rates of remission and response in placebo-controlled, randomized clinical trials for active UC and to identify factors influencing these rates., Methods: We performed a systematic review and meta-analysis of placebo-controlled, randomized clinical trials evaluating therapies for active UC identified from MEDLINE from 1966 through 2005., Results: Forty studies met the inclusion criteria. The pooled estimates of the placebo rates of remission and response were 13% (95% confidence interval, 9%-18%; range, 0%-40%; median, 12%) and 28% (95% confidence interval, 23%-33%; range, 0%-67%; median, 30%), respectively, both with significant heterogeneity. Studies that used more stringent definitions of outcomes had lower placebo rates of remission and response. Study duration, number of study visits, disease duration, baseline composite and rectal bleeding scores of the disease activity index, and inclusion of endoscopic mucosal healing as the remission definition all were associated with the placebo remission rate., Conclusions: Rates of remission in the placebo arm of UC clinical trials ranges from 0% to 40%. The placebo remission rates are influenced by the trial length, number of study visits, use of stricter remission definitions, and design features that enroll patients with more active disease. These factors should be considered when designing future placebo-controlled clinical trials in patients with active UC.