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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.).

ObjectiveWe developed a validated index for assessing histological disease activity in UC and established its responsiveness.MethodsTwo hundred biopsies were scored. The outcome was the Global Visual Evaluation (GVE). Eight histological features were tested. The Nancy index was developed by multiple linear regression and bootstrap process to create an index that best matched the GVE. Goodness of fit was assessed by the adjusted R squared (adjusted R2). The second step was the validation of the index: 100 biopsies were scored for the Nancy index by three pathologists from different centres. Inter-reader reliability was evaluated for each reader. The relationship between the change of the Nancy index and the Geboes index was assessed to assess the responsiveness.ResultsAfter backward selection with bootstrap validation, 3/8 items were selected: ulceration (adjusted R2=0.55), acute inflammatory infiltrate (adjusted R2=0.88) and chronic inflammatory infiltrate (adjusted R2=0.79). The Nancy index is defined by a 5-level classification ranging from grade 0 (absence of significant histological disease activity) to grade 4 (severely active disease). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.88 (95% CI 0.82 to 0.92) and the index had good inter-reader reliability (ICC=0.86 (0.81 to 0.99)). The correlation between the Nancy index and the Geboes score or the GVE was very good. The index had a good responsiveness with a high correlation between changes in the Geboes score and changes in the Nancy index (0.910 (0.813 to 0.955)).ConclusionsA three descriptor histological index has been validated for use in clinical practice and clinical trials.

In three phase 3 trials involving patients with ulcerative colitis, tofacitinib (an oral, small-molecule Janus kinase inhibitor) was more effective as induction and maintenance therapy than placebo. Infections were more common with tofacitinib. Ulcerative colitis is characterized by an increased frequency of bowel movements and bloody diarrhea, which has a negative effect on quality of life. 1 Current therapies for ulcerative colitis include mesalamine, glucocorticoids, thiopurines, and antagonists to tumor necrosis factor (TNF) and α4β7 integrin. 1 – 5 Many patients do not have a response to these therapies or have a response that is not sustained. Additional treatment options with new mechanisms of action are needed to increase efficacy rates. The Janus kinase (JAK) family comprises four intracellular tyrosine kinases — JAK1, JAK2, JAK3, and nonreceptor tyrosine-protein kinase 2 — that activate signal transducers and . . .

ObjectiveWe sought to evaluate COVID-19 clinical course in patients with IBD treated with different medication classes and combinations.DesignSurveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is a large, international registry created to monitor outcomes of IBD patients with confirmed COVID-19. We used multivariable regression with a generalised estimating equation accounting for country as a random effect to analyse the association of different medication classes with severe COVID-19, defined as intensive care unit admission, ventilator use and/or death.Results1439 cases from 47 countries were included (mean age 44.1 years, 51.4% men) of whom 112 patients (7.8%) had severe COVID-19. Compared with tumour necrosis factor (TNF) antagonist monotherapy, thiopurine monotherapy (adjusted OR (aOR) 4.08, 95% CI 1.73 to 9.61) and combination therapy with TNF antagonist and thiopurine (aOR 4.01, 95% CI 1.65 to 9.78) were associated with an increased risk of severe COVID-19. Any mesalamine/sulfasalazine compared with no mesalamine/sulfasalazine use was associated with an increased risk (aOR 1.70, 95% CI 1.26 to 2.29). This risk estimate increased when using TNF antagonist monotherapy as a reference group (aOR 3.52, 95% CI 1.93 to 6.45). Interleukin-12/23 and integrin antagonists were not associated with significantly different risk than TNF antagonist monotherapy (aOR 0.98, 95% CI 0.12 to 8.06 and aOR 2.42, 95% CI 0.59 to 9.96, respectively).ConclusionCombination therapy and thiopurines may be associated with an increased risk of severe COVID-19. No significant differences were observed when comparing classes of biologicals. These findings warrant confirmation in large population-based cohorts.MKH should be changed to MDK for co-last author line

Complex perianal fistulas in Crohn's disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn's disease. We did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (≥18 years) with Crohn's disease and treatment-refractory, draining complex perianal fistulas were randomly assigned (1:1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention-to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov, number NCT01541579. 212 patients were randomly assigned: 107 to Cx601 and 105 to placebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15·2%, 97·5% CI 0·2–30·3; p=0·024) and modified ITT populations (53 of 103 [51%] vs 36 of 101 [36%]; 15·8%, 0·5–31·2; p=0·021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine). Cx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohn's disease who did not respond to conventional or biological treatments, or both. TiGenix.

Cases of inflammatory bowel disease (IBD) during treatment with interleukin (IL)-17 antagonists have been reported from trials in psoriasis, psoriatic arthritis, and ankylosing spondylitis. The aim of this study was to assess the overall risk for development of IBD due to IL-17 inhibition. Systematic review and meta-analysis of studies conducted 2010-2018 of treatment with IL-17 antagonists in patients with psoriasis, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. We compared risk of IBD development in anti-IL-17 treated patients compared to placebo treatments. We also computed incident rates of IBD overall. A 'worst case scenario' defining subjects ambiguous for prevalent versus incident cases for the latter was also applied. Sixty-six studies of 14,390 patients exposed to induction and 19,380 patients exposed to induction and/or maintenance treatment were included. During induction, 11 incident cases of IBD were reported, whereas 33 cases were diagnosed during the entire treatment period. There was no difference in the pooled risk of new-onset IBD during induction studies for both the best-case [risk difference (RD) 0.0001 (95% CI: -0.0011, 0.0013)] and worst-case scenario [RD 0.0008 (95% CI: -0.0005, 0.0022)]. The risk of IBD was not different from placebo when including data from maintenance and long-term extension studies [RD 0.0007 (95% CI: -0.0023, 0.0036) and RD 0.0022 (95% CI: -0.0010, 0.0055), respectively]. The risk for development of IBD in patients treated with IL-17 antagonists is not elevated. Prospective surveillance of patients treated with IL-17 antagonists with symptom and biomarker assessments is warranted to assess for onset of IBD in these patients.

In this randomized trial comparing infliximab, azathioprine, and combination therapy in adults with moderate-to-severe Crohn's disease, infliximab and combination therapy were superior to azathioprine. Adverse events were similar in the three groups. In this randomized trial comparing infliximab, azathioprine, and combination therapy in adults with moderate-to-severe Crohn's disease, infliximab and combination therapy were superior to azathioprine. Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract that is defined by relapsing and remitting episodes, with progression over time to complications of stricture, fistulas, or abscesses. 1 Symptoms of mild-to-moderate disease are treated with mesalamine, budesonide, or systemic corticosteroids. 2 , 3 The therapeutic benefit of corticosteroids is frequently offset by side effects of prolonged exposure. 4 In addition, systemic corticosteroids and budesonide are not effective for maintenance therapy. 5 – 7 Azathioprine and 6-mercaptopurine are frequently prescribed for patients in whom first-line therapies fail — in particular, those who are dependent on or do not have a response to systemic corticosteroids. . . .

Background and aimsThe Simple Endoscopic Score for Crohn’s disease (SES-CD) is the primary tool for measurement of mucosal inflammation in clinical trials but lacks prognostic potential. We set to develop and validate a modified multiplier of the SES-CD (MM-SES-CD), which takes into consideration each individual parameter’s prognostic value for achieving endoscopic remission (ER) while on active therapy.MethodsIn this posthoc analysis of three CD clinical trial programmes (n=350 patients, baseline SES-CD ≥ 3 with confirmed ulceration), data were pooled and randomly split into a 70% training and 30% testing cohort. The MM-SES-CD was designed using weights for individual parameters as determined by logistic regression modelling, with 1-year ER (SES-CD < 3) being the dependent variable. A cut point score for low and high probability of ER was determined by using the maximum Youden Index and validated in the testing cohort.ResultsBaseline ulcer size, extent of ulceration and presence of non-passable strictures had the strongest association with 1-year ER as compared with affected surface area, with differential weighting of individual parameters across disease segments being observed during logistic regression. The MM-SES-CD was generated using this weighted regression model and demonstrated strong discrimination for ER in the training dataset (area under the receiver operator curve (AUC) 0.83, 95% CI 0.78 to 0.94) and in the testing dataset (AUC 0.82, 95% CI 0.77 to 0.92). In comparison to the MM-SES-CD scoring model, the original SES-CD score lacks accuracy (AUC 0.60, 95% CI 0.55 to 0.65) for predicting the achievement of ER.ConclusionsWe developed and internally validated the MM-SES-CD as an endoscopic severity assessment tool to predict one-year ER in patients with CD on active therapy.

Fecal microbiota transplantation (FMT) from healthy donors, which is an effective alternative for treatment of Clostridium difficile-associated disease, is being considered for several disorders such as inflammatory bowel disease, irritable bowel syndrome, and metabolic syndrome. Disease remission upon FMT is thought to be facilitated by an efficient colonization of healthy donor microbiota, but knowledge of the composition and temporal stability of patient microbiota after FMT is lacking. Five patients with moderately to severely active ulcerative colitis (Mayo score ≥6) and refractory to standard therapy received FMT via nasojejunal tube and enema. In addition to clinical activity and adverse events, the patients' fecal bacterial communities were monitored at multiple time points for up to 12 weeks using 16S rRNA gene-targeted pyrosequencing. FMT elicited fever and a temporary increase of C-reactive protein. Abundant bacteria from donors established in recipients, but the efficiency and stability of donor microbiota colonization varied greatly. A positive clinical response was observed after 12 weeks in one patient whose microbiota had been effectively augmented by FMT. This augmentation was marked by successive colonization of donor-derived phylotypes including the anti-inflammatory and/or short-chain fatty acid-producing Faecalibacterium prausnitzii, Rosebura faecis, and Bacteroides ovatus. Disease severity (as measured by the Mayo score) was associated with an overrepresentation of Enterobacteriaceae and an underrepresentation of Lachnospiraceae. This study highlights the value of characterizing temporally resolved microbiota dynamics for a better understanding of FMT efficacy and provides potentially useful diagnostic indicators for monitoring FMT success in the treatment of ulcerative colitis.

PF-00547659 is a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to selectively reduce lymphocyte homing to the intestinal tract. We aimed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe ulcerative colitis. This phase 2, randomised, double-blind, placebo-controlled clinical trial recruited patients aged 18–65 years from 105 centres in 21 countries, with a history (≥3 months) of active ulcerative colitis extending more than 15 cm beyond the anal verge (with a total Mayo score ≥6 and a Mayo endoscopic subscore ≥2) who had failed or were intolerant to at least one conventional therapy. Patients were stratified by previous anti-TNFα treatment, and randomly assigned by a computer-generated randomisation schedule to receive a subcutaneous injection of 7·5 mg, 22·5 mg, 75 mg, or 225 mg PF-00547659 or placebo at baseline, then every 4 weeks. Patients, investigators, and sponsors were blinded to the treatment. The primary endpoint was the proportion of patients achieving remission (total Mayo score ≤2 with no individual subscore >1 and rectal bleeding subscore ≤1) at week 12. The efficacy analysis included all patients who received at least one dose of the randomised treatment; the safety analysis was done according to treatment received. All p values were one-sided and multiplicity-adjusted. This study is registered with ClinicalTrials.gov, number NCT01620255. Between Nov 2, 2012, and Feb 4, 2016, we screened 587 patients; 357 were eligible and randomly assigned to receive placebo (n=73) or PF-00547659 at doses of 7·5 mg (n=71), 22·5 mg (n=72), 75 mg (n=71), or 225 mg (n=70). Remission rates at week 12 were significantly greater in three of four active-treatment groups than in the placebo group (2·7% [two of 73]): 7·5 mg (11·3% [eight of 71]), 22·5 mg (16·7% [12 of 72]), 75 mg (15·5% [11 of 71]), and 225 mg (5·7% [four of 70]). These rates corresponded to a stratum-adjusted (anti-TNFα-naive and anti-TNFα-experienced) risk difference versus placebo of 8·0% for 7·5 mg (90% CI 1·9 to 14, p=0·0425), 12·8% for 22·5 mg (5·6 to 19·9, p=0·0099), 11·8% for 75 mg (4·8 to 18·8, p=0·0119), and 2·6% for 225 mg (−1·2 to 6·4, p=0·1803). Four of 73 (5·5%) patients had a serious adverse event in the placebo group, 11 of 71 (15·5%) in the 7·5 mg group, one of 70 (1·4%) in the 22·5 mg group, three of 73 (4·1%) in the 75 mg group, and three of 70 (4·3%) in the 225 mg group. No safety signal was observed for the study drug. PF-00547659 was safe and well tolerated in this patient population, and better than placebo for induction of remission in patients with moderate to severe ulcerative colitis. The greatest clinical effects were observed with the 22·5 mg and 75 mg doses. Pfizer.