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BACKGROUND There are limited data of ustekinumab administered according to the doses recommended in the UNITI studies. AIM To assess the real-world, short-term effectiveness of ustekinumab in refractory Crohn's disease (CD) METHODS: Multicentre study of CD patients starting ustekinumab after June 2017 at the recommend dose (260, 390 or 520 mg based on weight ~6 mg/kg IV week 0 and 90 mg subcutaneously week 8). Values for Harvey-Bradshaw Index (HBI), C-reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 8 and 14. Demographic and clinical data, previous treatments, AEs and hospitalisations were documented. Possible predictors of clinical remission were examined. RESULTS Three hundred and five patients were analysed (≥2 previous anti-TNFα therapies 64% and vedolizumab 29%). At baseline, 217 (72%) had an HBI >4 points. Of these, 101 (47%) and 126 (58%) achieved clinical remission at weeks 8 and 14, respectively. FC levels returned to normal (

The safety and efficacy of tofacitinib in Crohn's disease (CD) has been studied in 2 phase II trials in patients with moderate-to-severe CD with no new safety signals observed, but no significant difference from placebo in the primary efficacy endpoint of clinical response.1-3 However, post hoc analyses and smaller studies have observed clinical and biologic response to tofacitinib in patients with CD.2,4,5 There is a paucity of real-world effectiveness and safety data for tofacitinib in non-Food and Drug Administration label usage in patients with CD and patients with inflammatory bowel disease-unclassified (IBD-U).

Background and Aims Inflammation of the pouch after ileal pouch-anal anastomosis (IPAA) can significantly impact quality of life and be difficult to treat. We assessed the effectiveness and safety of vedolizumab in Crohn’s disease (CD) of the pouch and chronic antibiotic-dependent or antibiotic-refractory pouchitis. Methods This was a retrospective, multicenter cohort study at 5 academic referral centers in the United States. Adult patients with endoscopic inflammation of the pouch who received vedolizumab were included. The primary outcome was clinical response at any time point. Secondary outcomes included clinical remission, endoscopic response, and remission. Univariate analysis and multivariate analysis were performed for the effect of the following variables on clinical response: fistula, onset of pouchitis less than 1 year after IPAA, younger than 35 years old, gender, previous tumor necrosis factor inhibitor-alpha use, and BMI >30. Results Eighty-three patients were treated with vedolizumab for inflammation of the pouch between January 2014 and October 2017. Median follow-up was 1.3 years (interquartile range 0.7–2.1). The proportion of patients that achieved at least a clinical response was 71.1%, with 19.3% achieving clinical remission. Of the 74 patients with a follow-up pouchoscopy, the proportion of patients with endoscopic response and mucosal healing was 54.1% and 17.6%, respectively. Patients who developed pouchitis symptoms less than 1 year after undergoing IPAA were less likely to respond to vedolizumab, even after controlling for other risk factors. Conclusions Vedolizumab is safe and effective in the management of CD of the pouch and chronic pouchitis. Further studies are needed to compare vedolizumab with other biologic therapies for pouchitis and CD of the pouch.

BACKGROUND Anti-drug antibodies (ADAbs) may decrease the efficacy of biologics and increase the risk of adverse events. A single positive test may not preclude further treatment because of variations in assays used, test timing, and patient variables. We evaluated the longitudinal patterns of immunogenicity during 7 years of antitumor necrosis factor-alpha drug certolizumab pegol (CZP) treatment for moderate-to-severe Crohn's disease. METHODS PRECiSE 3 patients (n = 595) received open-label CZP 400 mg every 4 weeks up to 7 years. CZP-ADAb expression, plasma CZP concentration, Harvey-Bradshaw Index, C-reactive protein, and fecal calprotectin concentrations were measured multiple times. Longitudinal data, examined for CZP-ADAb positivity and categorized as transient (with temporary/no effect on CZP concentration), persistent, or negative, were correlated with clinical and biological variables. RESULTS Of the CZP-ADAb-positive patients, 40 (22.6%) had transient CZP-ADAbs and 94 (77.4%) had persistent CZP-ADAbs. Demographic characteristics were similar between groups. Median C-reactive protein and fecal calprotectin were higher (P < 0.05 at some visits) and plasma CZP concentrations were significantly lower (P < 0.0001 at all visits) in the persistent CZP-ADAb-positive group relative to the CZP-ADAb-negative group. Transient CZP-ADAb-positive and CZP-ADAb-negative patients had similar plasma CZP, C-reactive protein, and fecal calprotectin concentrations. Median Harvey-Bradshaw Index scores and rates of adverse events were similar among groups. CONCLUSIONS This analysis demonstrates that persistent CZP-ADAb has negative effects on drug levels and efficacy, whereas transient expression may not. Serial measurements may be needed to characterize ADAb positivity. www.clinicaltrials.gov, Number NCT00160524.

Crohn's disease is a lifelong, incurable inflammatory disease of the gastrointestinal tract that often arises in the earlier decades of life and is characterized by periods of exacerbation and remission. Tumor necrosis factor (TNF) α has a central role in the pathogenesis of inflammatory bowel diseases, and specific inhibition of this pleotropic cytokine with biological anti-TNF agents has been a major advancement in the treatment of these diseases including Crohn's disease.1,2 Anti-TNF therapy is generally well tolerated.3–5 However, because these agents have immunosuppressive properties, long-term use may increase the risk of serious infections,6 and careful consideration is given to the initiation of therapy. Only 3 anti-TNF therapies, including infliximab, adalimumab, and certolizumab pegol, are currently approved for the treatment of moderate to severe Crohn's disease in the United States. In randomized controlled trials, approximately 40% to 60% of patients with Crohn's disease had an initial response to induction therapy with anti-TNF therapy during the first 2 to 6 weeks, and of those approximately 40% to 60% were in remission after 6 months of therapy.3–5,7 However, the duration of clinical response varies widely among patients. Results of PRECiSE 2, a randomized, placebo-controlled study of certolizumab pegol maintenance therapy in patients with moderate to severe Crohn's disease, showed that approximately 40% of initial responders lost response within 6 months after treatment initiation.5 In clinical practice, 30% to 40% of patients treated with adalimumab required dose escalation; however, approximately one-third of those who received increased doses failed to maintain responses longer than 6 months.8 These examples illustrate that both primary and secondary failure to anti-TNF therapy remain significant challenges in the treatment of patients with Crohn's disease. Given the need for long-term maintenance therapy and the small number of available anti-TNF therapies, identifying strategies to maximize the benefit that a patient can derive from each agent is important. Recent studies have shown that reinduction therapy with another9 or the same10 anti-TNF agent in patients with secondary treatment failure provides clinically important short-term benefits. However, the longer-term benefit of reintroducing the same therapy to patients with primary and secondary treatment failure, including patients who previously received as little as 1 dose of induction treatment, has not been explored. Certolizumab pegol is a recombinant, humanized, polyethylene glycol–conjugated antigen-binding antibody fragment (Fab') with specificity for human TNFα. Two randomized, double-blind, placebo-controlled phase 3 studies, PRECiSE 17 and PRECiSE 2,5 demonstrated that certolizumab pegol is effective in the induction and maintenance of clinical response and remission in patients with moderate to severe Crohn's disease. Unlike patients in PRECiSE 2, who were randomized to maintenance treatment with placebo or certolizumab pegol after responding to 6 weeks of induction therapy with certolizumab pegol, patients in PRECiSE 1 were randomized to consecutive induction and maintenance treatment with either placebo or certolizumab pegol at the start of the trial. Patients who completed PRECiSE 1 or PRECiSE 2 were eligible for inclusion in PRECiSE 3, an open-label, 7-year extension study.11 In contrast, PRECiSE 4 (NCT00160706) was an open-label extension study for patients who withdrew from either treatment arm of PRECiSE 1 or PRECiSE 2 owing to exacerbation of Crohn's disease and was designed to assess the safety and efficacy of chronic certolizumab pegol therapy for up to 7 years. Here, we report efficacy and safety outcomes from the PRECiSE 4 study, which included patients with no previous exposure to certolizumab pegol, as well as patients with primary or secondary certolizumab pegol treatment failure.

SUMMARYBackground Clinical factors were previously identified as predictors of short-term treatment efficacy in Crohn's disease (CD). The PRECiSE 3 (P3) 7-year trial provides an opportunity to study predictors of short- and long-term clinical remission among CD patients treated with certolizumab pegol (CZP). Aim To identify factors that influence long-term remission of CD with CZP treatment. Methods Patients who had completed placebo-controlled studies (PRECiSE 1/PRECiSE 2, P1/P2) enrolled in P3 and received open-label CZP 400 mg every 4 weeks up to 7 years. Baseline predictors included, but were not limited to, smoking status, disease duration, prior inflammatory bowel disease (IBD) surgery, Harvey–Bradshaw Index (HBI), albumin, haematocrit and CZP exposure; association with time to initial remission (HBI ≤4) was tested for patients who received CZP in P1/P2; time to loss of remission/frequency of maintenance of remission was also tested. Univariate analyses and multivariate Cox or logistic regression models were used. Results Predictors for initial remission (N = 377) included age, haematocrit, prior IBD surgery and entry HBI (P

Abdominal and pelvic abscesses are a common complication of Crohn's disease. We studied the effect of the initial choice of therapy on time to resolution of abdominal and pelvic abscesses.We recorded clinical, laboratory, and radiographic data on all adult patients with Crohn's disease and abdominal or pelvic abscesses treated at our institution from 1991 to 2001 and followedor = 1 yr. Univariate analysis identified variables associated with initial choice of drainage modality. These variables were included in a Cox regression model to identify factors independently associated with time to resolution.Of 66 episodes identified, surgery was the initial modality in 29 and percutaneous drainage in 37. Median time to resolution was not different between surgical drainage (25.0 days, range 0-240) and percutaneous drainage (21.5 days, range 0-182) (p = 0.084). Older age, longer duration of symptoms prior to drainage, no fistula identified radiographically, immune modulator use, no rebound tenderness, and admission to the medical service were factors associated with percutaneous drainage as initial modality. These factors, when incorporated in a Cox regression model, did not significantly affect the time to resolution. Days from onset of symptoms to radiographic diagnosis or drainage were independently associated with time to resolution of the abscess.Time to resolution of abdominal or pelvic abscesses in Crohn's disease is similar with percutaneous drainage and surgery. One-third of patients treated with percutaneous drainage required surgery within 1 yr. Earlier intervention for abdominal and pelvic abscesses is associated with shorter time to resolution.

BackgroundThe efficacy and safety of certolizumab pegol (CZP) in moderate-to-severe Crohn's disease were demonstrated in two 26-week double-blind studies (PRECiSE 1 & 2). AimTo report the safety and efficacy outcomes of long-term, CZP therapy from PRECiSE 3, in which patients received treatment up to 7years treatment. MethodsPatients completing PRECiSE 1 or 2 were eligible to enter PRECiSE 3 in which they received CZP 400mg, open-label, every 4weeks (without additional induction therapy) for up to 7years, for up to 91 doses from study start. Safety (adverse events, including infections and malignancies) and efficacy (Harvey-Bradshaw Index, faecal calprotectin, C-reactive protein) were prospectively monitored. Remission was analysed using observed cases, last observation carried forward imputation and nonresponder imputation. ResultsA total of 595 patients entered the study; 117 (20%) completed 7years. Discontinuation rates were 29.2%, 13.6%, 16.1%, 7.9%, 5.0%, 4.5% and 3.9% (years 1-7 respectively). During 1920 patient-years of exposure to CZP, no new safety signals were observed. Incidence rates (new cases/100 patient-years) for serious infections and malignant neoplasms were 4.37 and 1.06 respectively. No lymphoproliferative malignancies were reported. Clinical remission rates were 68% at each year (observed cases); rates by last observation carried forward and nonresponder imputation were 58% and 45% at year 1, 56% and 26% at year 3 and 55% and 13% at year 7 respectively. ConclusionCertolizumab pegol was well tolerated in the long-term treatment of Crohn's disease, with sustained remission in some patients continuing in the study for up to 7years. ClinicalTrials.gov identifier NCT00552058.

The therapy of Crohn's disease is constantly evolving. It is widely recognized that clinical assessment does not stage disease activity accurately and that endoscopic healing is associated with improved long-term outcomes. Disease management is therefore transitioning to a new paradigm that includes direct assessment of disease severity (endoscopically in most patients), followed by assessment of mucosal healing. New approaches have helped optimize the use of the thiopurines, methotrexate and anti-TNF agents. Novel agents with different mechanisms of action are expanding our therapeutic armamentarium. The major challenge of the future will be to identify patient subgroups best suited to particular therapeutic approaches. In the meantime, studies of comparative effectiveness will be crucial in positioning therapies relative to each other.

transhepatic cholangiography (PTC) with temporary biliary stenting was performed within a month of the new diagnosis for worsening cholestasis. Three months later, mycophenolate mofetil (Cellcept) was started for persistently increased transaminases. She finally began to respond with significant decrease in serum transaminase and alkaline phosphatase levels. After 3 years of successful management, she developed diarrhea and abdominal cramping. Colonoscopy revealed extensive patchy mucosal inflammation throughout the colon and terminal ileum. Mucosal biopsies demonstrated extensive crypt distortion, focal cryptitis, increased chronic inflammation, fibrino-inflammatory exudates and erosion establishing a diagnosis of Crohn’s disease (CD) ( fig. 1 ). Contrasted CT scan of the abdomen and pelvis revealed diffuse thickening of terminal ileum, cecum, ascending and transverse colonic wall and pericolic stranding consistent with active inflammatory bowel disease. It also demonstrated signs of liver cirrhosis (based on the increased caudate to right lobe ratio) as well as intraand extrahepatic biliary dilation ( fig. 2 a, b). Budesonide 9 mg daily was added to treat active CD and prednisone was discontinued. She remained symptomatic with continued diarrhea and further deterioraDear Sir Autoimmune hepatitis-primary sclerosing cholangitis (AIH-PSC) overlap syndrome is characterized by features of both conditions. Association of AIH-PSC overlap syndrome with ulcerative colitis (UC) is well recognized but is rarely seen with Crohn’s disease (CD). We report a case of a young African-American woman with AIH-PSC overlap syndrome complicated by CD that illustrates the approach to diagnosis and management of the condition. A brief discussion of the topic follows the case presentation.

BACKGROUND & AIMS: Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through γ-chain-containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn's disease. METHODS: Patients (N = 139; age, ≥18 y) with moderate-to-severe active Crohn's disease were assigned randomly to groups given 1 mg (n = 36), 5 mg (n = 34), or 15 mg (n = 35) tofacitinib or placebo (n = 34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary end point was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn's Disease Activity Index score of ≥70 points [Response-70]). Secondary end points included clinical remission (Crohn's Disease Activity Index score of

Background: Published data suggest a link between obesity and adverse outcomes in Crohn ’ s disease (CD). We aimed to test the hypothesis that obese CD patients would be more likely than non-obese CD patients to have poor surgical outcome when undergoing surgery for a complication of CD. Methods: We designed a retrospective cohort study to test our hypothesis. The population comprised of adult CD patients who underwent CD related surgery at a tertiary referral center. The exposed and unexposed cohorts were represented by patients who were obese vs. non-obese at the pre-op visit respectively. Outcome was represented by successful vs. unsuccessful surgical outcome as deemed by the treating clinician. Results: Ninety CD patients were eligible for inclusion into this cohort study of which 36 were obese (exposed cohort) and 54 were non-obese (unexposed cohort). Among obese CD patients, 64% had an unsuccessful surgical outcome vs. 41% with unsuccessful surgical outcome among the non-obese. Based on unadjusted bivariate analysis, potential confounders identified included age and type of surgery. Gender distribution, disease duration, ethnicity, tobacco use, steroid use, traditional and biological immune modulator use and clinical disease activity were similar between the two groups. Logistic regression adjusted for age and type of surgery revealed that obese CD patients were approximately 2.5 times more likely to have a poor surgical outcome than patients with CD who were not obese (P = 0.05 OR 2.53 95% CI 0.99 - 6.52). BMI as a continuous variable (adjusted for age and type of surgery) appeared to be associated with poor surgical outcome (P = 0.06 OR 1.07 95% CI 0.99 - 1.15). Conclusions: Obesity may be associated with poor surgical outcome in CD patients. doi: http://dx.doi.org/10.4021/gr553w