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Upadacitinib, an oral selective Janus kinase (JAK) inhibitor, is under investigation for the treatment of Crohn's disease. In two phase 3 induction trials (U-EXCEL and U-EXCEED), we randomly assigned patients with moderate-to-severe Crohn's disease to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks. Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn's Disease [SES-CD; range, 0 to 56, with higher scores indicating more severe disease] of >50% from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]). A total of 526 patients underwent randomization in U-EXCEL, 495 in U-EXCEED, and 502 in U-ENDURE. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons). Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib. Upadacitinib induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn's disease. (Funded by AbbVie; U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.).

Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16–80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12–29; 152/336) with risankizumab 600 mg and 42% (17%, 8–25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14–30; 146/336) with risankizumab 600 mg and 41% (19%, 11–27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21–35; 135/336) with risankizumab 600 mg and 32% (20%, 14–27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13–31; 80/191) with risankizumab 600 mg and 40% (21%, 12–29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6–24; 66/191) with risankizumab 600 mg and 40% (20%, 12–29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10–25; 55/191) with risankizumab 600 mg and 34% (23%, 15–31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. AbbVie.

The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis. This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries. Eligible patients were aged 18–75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522. Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1–19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6–12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0–35·9; p<0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0–20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment. Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. Gilead Sciences.

The changing epidemiology of inflammatory bowel disease (IBD) across time and geography suggests that environmental factors play a major role in modifying disease expression. Disease emergence in developing nations suggests that epidemiological evolution is related to westernisation of lifestyle and industrialisation. The strongest environmental associations identified are cigarette smoking and appendectomy, although neither alone explains the variation in incidence of IBD worldwide. Urbanisation of societies, associated with changes in diet, antibiotic use, hygiene status, microbial exposures and pollution have been implicated as potential environmental risk factors for IBD. Changes in socioeconomic status might occur differently in different geographical areas and populations and, consequently, it is important to consider the heterogeneity of risk factors applicable to the individual patient. Environmental risk factors of individual, familial, community-based, country-based and regionally based origin may all contribute to the pathogenesis of IBD. The geographical variation of IBD provides clues for researchers to investigate possible environmental aetiological factors. The present review aims to provide an update of the literature exploring geographical variability in IBD and to explore the environmental risk factors that may account for this variability.

Therapeutic drug monitoring (TDM) of biologics is a rapidly evolving field. We aimed to provide a consensus statement regarding the clinical utility of TDM for biologics in inflammatory bowel disease (IBD). A modified Delphi method was applied to develop consensus statements. A comprehensive literature review was performed regarding TDM of biologic therapies in IBD, and 45 statements were subsequently formulated on the potential application of TDM in IBD. The statements, along with literature, were then presented to a panel of 10 gastroenterologists with expertise in IBD and TDM who anonymously rated them on a scale of 1–10 (1 = strongly disagree and 10 = strongly agree). An expert consensus development meeting was held virtually to review, discuss, refine, and reformulate statements that did not meet criteria for agreement or that were ambiguous. During the meeting, additional statements were proposed. Panelists then confidentially revoted, and statements rated ≥7 by 80% or more of the participants were accepted. During the virtual meeting, 8 statements were reworded, 7 new statements were proposed, and 19 statements were rerated. Consensus was finally reached in 48/49 statements. The panel agreed that reactive TDM should be used for all biologics for both primary nonresponse and secondary loss of response. It was recommended that treatment discontinuation should not be considered for infliximab or adalimumab until a drug concentration of at least 10–15 μg/mL was achieved. Consensus was also achieved regarding the utility of proactive TDM for anti–tumor necrosis factor therapy. It was recommended to perform proactive TDM after induction and at least once during maintenance. Consensus was achieved in most cases regarding the utility of TDM of biologics in IBD, specifically for reactive and proactive TDM of anti–tumor necrosis factors.

Natural history studies provide invaluable data on the disease course. First, they help define the end points for clinical trials that are designed to test drugs for the end point of disease modification in chronic disabling diseases. Natural history studies can also help to identify subsets of patients in whom the disease prognosis can be stratified according to clinical features. This comprehensive review summarizes our current knowledge of the natural history of Crohn's disease in adults as reported in population-based studies that include long-term follow-up results. We conducted a literature search of English and non-English language publications listed in the electronic databases of MEDLINE (source PUBMED, 1935 to December 2008). One-third of the patients had ileitis, colitis, or ileocolitis at the time of diagnosis. Disease location remained broadly stable over time. Up to one-third of the patients had evidence of a stricturing or penetrating intestinal complication at diagnosis, and half of all patients had experienced an intestinal complication within 20 years after diagnosis. Ten percent of the patients had prolonged clinical remission. Steroid dependency occurred in one-third of the patients, and surgery was required in one-third after initiation of steroid therapy. The annual incidence of hospitalizations was 20%. Half of the patients required surgery within 10 years after diagnosis. The risk of postoperative recurrence was 44-55% after 10 years. Crohn's disease is a disabling condition over time. The impact of changing treatment paradigms with increased use of immunosuppressants and biological agents on its natural history is poorly known.

Abstract Background This study sought to re-estimate the cumulative incidence of perianal or rectovaginal fistulas and the associated proctectomy rate in the prebiologic era vs the biologic era using a population-based cohort of Crohn's disease (CD) patients. Methods The medical records of 414 residents of Olmsted County, Minnesota, who were diagnosed with CD between 1970 and 2010 were reviewed. The cumulative incidence of perianal or rectovaginal fistulas from time of CD diagnosis and the cumulative rate of proctectomy from date of first perianal or rectovaginal fistula diagnosis were estimated using the Kaplan-Meier method. Results Eighty-five patients (20.5%) diagnosed with CD between 1970 and 2010 had at least 1 perianal or rectovaginal fistula episode between January 1, 1970, and June 30, 2016. The cumulative incidence of perianal or rectovaginal fistulas was 18% after 10 years, 23% after 20 years, and 24% after 30-40 years from CD diagnosis. The cumulative incidence of perianal or rectovaginal fistulas was significantly lower in patients diagnosed in 1998 or after than in patients diagnosed before 1998 (P = 0.03, log-rank). Among 85 patients developing perianal or rectovaginal fistulas, 16 patients (18.8%) underwent proctectomy for the treatment of perianal or rectovaginal fistulas during follow-up. Conclusions In a population-based inception cohort of CD, one-fifth of patients were diagnosed with at least 1 perianal or rectovaginal fistula. The cumulative probability of perianal or rectovaginal fistulizing disease has decreased over time. Video Abstract 10.1093/ibd/izy329_video1 izy329.video1 5850901975001

Ileal pouch–anal anastomosis (IPAA) has become the surgical procedure of choice for patients with chronic ulcerative colitis. No study to date has examined functional and quality-of-life outcomes 30 years after pouch construction.MethodsUsing data from a prospectively maintained database with annually distributed questionnaires, functional outcomes, pouch complications, and quality of life after IPAA were determined.ResultsOverall, 93.3% of patients had a functioning pouch at 30 years. Stool frequency during the day increased slightly from a mean of 5.7 (SD, 2.3) at 1 year to 6.2 (SD, 2.9) at 30 years (P < 0.001); nighttime frequency also increased slightly from 1.5 (SD, 1.2) to 2.1 (SD, 1.2) (P < 0.001). Pouch outcomes and stool frequency were significantly associated with diagnosis, being worse in patients with Crohn's disease, but were minimally associated with age greater than 65 years. After IPAA, the 30-year cumulative probability of pouchitis, stricture, obstruction, and fistula were 80.2%, 56.7%, 44.0%, and 15.8%, respectively. Quality of life scores remained stable over the 30 years.ConclusionsIPAA is a durable operation for patients requiring proctocolectomy for chronic ulcerative colitis and indeterminate colitis. The functional outcomes and quality of life remained relatively unchanged over the 30 years after IPAA underscoring the longevity of pouches.

Background Tumor necrosis factor (TNF)-α inhibitors are increasingly being used in inflammatory bowel disease (IBD). Because this chronic intestinal disorder often affects women of fertile age, it is essential to assess the effect of biologics on pregnancy outcome. Methods We performed a systematic review of the English-language literature to investigate if treatment with TNF-α blockers during pregnancy in women with IBD increases the risk of spontaneous abortions, preterm delivery, stillbirth, low birth weight, congenital malformations, or risk of infections in the offspring. Of 552 articles and abstracts reviewed, 58 articles or abstracts with unique content were identified and included in this systematic review. However, most presentations were case reports or case series supplied by a limited number of observational studies. No randomized controlled studies were available. Results TNF-α inhibitors do not seem to affect either outcome of pregnancy in mothers with IBD, or the outcome in the offspring (congenital malformations and immunosuppression). Further, recent data have not identified any increased risk of infections in the first year of life in the offspring of mothers who received biologics, even in combination with immunomodulators (thiopurines). Conclusions From the present systematic review, no association was found between administration of TNF inhibitors for IBD during pregnancy and adverse pregnancy outcome or congenital abnormalities. Further, no increased relative risk of infections has been reported in the first year of life in offspring of mothers who received biologics. Biologics should be discontinued during pregnancy solely if the IBD is in remission using the same stopping criteria as for patients with IBD in general, as uncontrolled activity of IBD may expose the mother and child to a risk greater than those only potentially coming from the use of TNF-α inhibitors. In such cases, inoculation of the offspring with live vaccines is contraindicated until the biologic agent is no longer detectable in the child’s circulation.

Abstract Background Fistulas occur in about 25% of patients with Crohn's disease (CD) and can be difficult to treat. The aim of this consensus was to provide guidance for the management of patients with perianal fistulizing CD. Methods A systematic literature search identified studies on the management of fistulizing CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform using a modified Delphi process, then finalized, and voted on by a group of specialists. Results The quality of evidence for treatment of fistulizing CD was generally of very low quality, and because of the scarcity of good randomized controlled trials (RCTs), these consensus statements generally provide conditional suggestions (5 of 7 statements). Imaging and surgical consultations were recommended in the initial assessment of patients with active fistulizing CD, particularly those with complicated disease. Antibiotic therapy is useful for initial symptom control. Antitumor necrosis factor (anti-TNF) therapy was recommended to induce symptomatic response, and continued use was suggested to achieve and maintain complete remission. The use of concomitant immunosuppressant therapies may be useful to optimize pharmacokinetic parameters when initiating anti-TNF therapy. When there has been an inadequate symptomatic response to medical management strategies, surgical therapy may provide effective fistula healing for some patients. Conclusions Optimal management of perianal fistulizing CD requires a collaborative effort between gastroenterologists and surgeons and may include the evidence-based use of existing therapies, as well as surgical assessments and interventions when needed. 10.1093/ibd/izy247_video1 izy247.video1 5978518763001