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Lay Summary In this retrospective cohort study, we demonstrated that dose intensification of ustekinumab to every 4 or every 6 weeks was effective in both achieving and maintaining clinical remission for >40% of inflammatory bowel disease patients for up to 24 months.

Crohn's disease is a chronic inflammatory disease that can affect any portion of the gastrointestinal tract. Associated symptoms can vary based on the severity of disease, extent of involvement, presence of extraintestinal manifestations, and development of complications. Diagnosis is based on a constellation of findings. Many diseases can mimic Crohn's disease and lead to diagnostic conundrums. These include entities associated with the gastrointestinal luminal tract, vascular disease, autoimmune processes, various infections, malignancies and complications, drug- or treatment-induced conditions, and genetic diseases. Careful consideration of possible causes is necessary to establish the correct diagnosis.

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Real-world data comparing the effectiveness of tofacitinib to ustekinumab are limited. We compared 52-week outcomes of tofacitinib vs ustekinumab for UC after antitumor necrosis factor (anti-TNF) failure. Methods In this retrospective cohort study, adults initiated tofacitinib or ustekinumab for UC after anti-TNF failure May 1, 2018 to April 1, 2021, at a US academic medical center. The primary outcome was steroid-free clinical remission (SFCR) at 12 and 52 weeks. The secondary outcome was drug survival (ie, time to drug discontinuation due to nonresponse). Adverse events (AEs) were also assessed. Results Sixty-nine patients initiated tofacitinib, and 97 patients initiated ustekinumab with median follow-up of 88.0 and 62.0 weeks, respectively. After inverse probability of treatment-weighted logistic and Cox regression, there was no association of tofacitinib vs ustekinumab with SFCR at 12 weeks (odds ratio, 1.65; 95% CI, 0.79-3.41), SFCR at 52 weeks (odds ratio, 1.14; 95% CI, 0.55-2.34), or drug survival (hazard ratio, 1.37; 95% CI, 0.78-2.37). Kaplan-Meier analysis demonstrated no separation in drug survival curves. Regression results were similar after excluding patients with prior tofacitinib or ustekinumab exposure. During available follow-up, 17 AEs were reported for tofacitinib (most commonly shingles, n = 4), and 10 AEs were reported for ustekinumab (most commonly arthralgia and rash, each n = 2). Two patients discontinued treatment due to AEs (1 tofacitinib for elevated liver enzymes, 1 ustekinumab for arthralgia). Conclusions In a real-world UC cohort, tofacitinib and ustekinumab demonstrated similar effectiveness at 52 weeks. Adverse events were consistent with the known safety profiles of these agents.

Fecal microbiota transplantation (FMT) is a promising therapeutic modality for the treatment and prevention of metabolic disease. We previously conducted a double-blind, randomized, placebo-controlled pilot trial of FMT in obese metabolically healthy patients in which we found that FMT enhanced gut bacterial bile acid metabolism and delayed the development of impaired glucose tolerance relative to the placebo control group. Therefore, we conducted a secondary analysis of fecal samples collected from these patients to assess the potential gut microbial species contributing to the effect of FMT to improve metabolic health and increase gut bacterial bile acid metabolism. Fecal samples collected at baseline and after 4 weeks of FMT or placebo treatment underwent shotgun metagenomic analysis. Ultra-high-performance liquid chromatography-mass spectrometry was used to profile fecal bile acids. FMT-enriched bacteria that have been implicated in gut bile acid metabolism included Desulfovibrio fairfieldensis and Clostridium hylemonae. To identify candidate bacteria involved in gut microbial bile acid metabolism, we assessed correlations between bacterial species abundance and bile acid profile, with a focus on bile acid products of gut bacterial metabolism. Bacteroides ovatus and Phocaeicola dorei were positively correlated with unconjugated bile acids. Bifidobacterium adolescentis, Collinsella aerofaciens, and Faecalibacterium prausnitzii were positively correlated with secondary bile acids. Together, these data identify several candidate bacteria that may contribute to the metabolic benefits of FMT and gut bacterial bile acid metabolism that requires further functional validation.

Autoimmune liver disease (AILD) spans a spectrum of chronic disorders affecting the liver parenchyma and biliary system. Three main categories of AILD are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). This review condenses the presentation and discussions of the Single Topic Conference (STC) on AILD that was held in Ottawa, Ontario, in November 2019. We cover generalities regarding disease presentation and clinical diagnosis; mechanistic themes; treatment paradigms; clinical trials, including approaches and challenges to new therapies; and looking beyond traditional disease boundaries. Although these diseases are considered autoimmune, the etiology and role of environmental triggers are poorly understood. AILDs are progressive and chronic conditions that affect survival and quality of life. Advances have been made in PBC treatment because second-line treatments are now available (obeticholic acid, bezafibrate); however, a significant proportion still present suboptimal response. AIH treatment has remained unchanged for several decades, and data suggest that fewer than 50% of patients achieve a complete response and as many as 80% develop treatment-related side effects. B-cell depletion therapy to treat AIH is in an early stage of development and has shown promising results. An effective treatment for PSC is urgently needed. Liver transplant remains the best option for patients who develop decompensated cirrhosis or hepatocellular carcinoma within specific criteria, but recurrent AILD might occur. Continued efforts are warranted to develop networks for AILD aimed at assessing geo-epidemiological, clinical, and biochemical differences to capture the new treatment era in Canada.

Background: Factors influencing recurrence risk in primary Clostridioides difficile infection (CDI) are poorly understood, and tools predicting recurrence are lacking. Perturbations in bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis. Aims: To define stool BA dynamics in patients with primary CDI and explore signatures predicting recurrence Methods Weekly stool samples were collected from patients with primary CDI from the last day of anti-CDI therapy until recurrence or, otherwise, through 8 weeks post-completion. Ultra-high performance liquid chromatography-mass spectrometry was used to profile BAs; stool bile salt hydrolase (BSH) activity was measured to determine primary BA bacterial deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in patients with recurrence versus those without, and to assess faecal BAs as predictive markers for recurrence. Results: Twenty (36%) of 56 patients (median age: 57, 64% male) had recurrence; 80% of recurrences occurred within the first 9 days post-antibiotic treatment. Principal component analysis of stool BA profiles demonstrated clustering by recurrence status and post-treatment timepoint. Longitudinal faecal BA trajectories showed recovery of secondary BAs and their derivatives only in patients without recurrence. BSH activity increased over time only among non-relapsing patients (β = 0.056; likelihood ratio test p = 0.018). A joint longitudinal-survival model identified five stool BAs with area under the receiver operating characteristic curve >0.73 for predicting recurrence within 9 days post-CDI treatment. Conclusions: Gut BA metabolism dynamics differ in primary CDI patients between those developing recurrence and those who do not. Individual BAs show promise as potential novel biomarkers to predict CDI recurrence.

Background The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. Methods Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. Results Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. Conclusions The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.

Clostridioides difficile infection (CDI) harms a large proportion of patients with cirrhosis. Fecal microbiota transplantation (FMT) is recommended for recurrent CDI, but its effects in patients with cirrhosis have not been established. We performed a multicenter observational study to evaluate the efficacy and safety of FMT for CDI in patients with cirrhosis.We performed a retrospective study of 63 adults with cirrhosis (median model for end-stage liver disease score, 14.5; 24 patients with decompensated cirrhosis) who underwent FMT for CDI from January 2012 through November 2018 at 8 academic centers in the United States, Canada, and Italy. We collected data on patient demographics and characteristics of cirrhosis, CDI, and FMT from medical records and compared differences among patients with different severities of cirrhosis, and FMT successes vs failures at the 8-week follow-up evaluation. We also obtained data on adverse events (AEs) and severe AEs within 12 weeks of FMT.Patients underwent FMT for recurrent CDI (55 of 63; 87.3%), severe CDI (6 of 63; 9.5%), or fulminant CDI (2 of 63; 3.2%) primarily via colonoscopy (59 of 63; 93.7%) as outpatients (47 of 63; 76.8%). FMT success was achieved for 54 patients (85.7%). Among FMT failures, a higher proportion used non-CDI antibiotics at the time of FMT (44.4% vs 5.6%; P.001), had Child-Pugh scores of B or C (100% vs 37.7%; P.001), used probiotics (77.8% vs 24.1%; P = .003), had pseudomembranes (22.2% vs 0; P = .018), and underwent FMT as inpatients (45.5% vs 19%; P = .039), compared with FMT successes. In multivariable analysis, use of non-CDI antibiotics at the time of FMT (odds ratio, 17.43; 95% CI, 2.00-152.03; P = .01) and use of probiotics (odds ratio, 11.9; 95% CI, 1.81-78.3; P = .01) were associated with a greater risk of FMT failure. FMT-related AEs occurred in 33.3% of patients (21 of 63)-most were self-limited abdominal cramps or diarrhea. There were only 5 severe AEs that possibly were related to FMT; none involved infection or death.In a retrospective study, we found FMT to be safe and effective for the treatment of CDI in patients with cirrhosis.

Background Recurrent or chronic antibiotic therapy is a therapeutic hallmark of chronic antibiotic-dependent pouchitis (CADP) or Crohn’s-like disease of the pouch. Antibiotics alter the gut microbiome, which may increase the risk of Clostridioides difficile infection (CDI). The aim of this study was to determine the prevalence of CDI in patients with CADP and Crohn’s-like disease of the pouch. Methods We conducted a retrospective cohort study of patients with CADP or Crohn’s-like disease of the pouch at a tertiary academic medical center. The primary outcome was prevalence of CDI. Secondary outcomes included antibiotic therapy at the time of CDI diagnosis, treatment regimens for CDI, and subsequent outcomes. Results Overall, 18 of 198 (9.1%) included patients developed CDI. Treatment with antibiotics at the time of CDI diagnosis occurred in 7 of 18 (39%) patients. Preoperative history of CDI was significantly associated with increased risk of developing CDI following ileal pouch anal anastomosis (IPAA) compared with those with no prior history of CDI (12 of 18 [67%] vs 11 of 180 [6%]; P Conclusion Although chronic inflammatory conditions of the pouch arise postoperatively, the prevalence of CDI in this population appears to be similar compared with the general population of patients with inflammatory bowel disease prior to and post IPAA. Preoperative CDI appears to be the greatest risk for postoperative CDI and may require extra vigilance in the assessment of CDI after IPAA.

1.AbstractBackgroundFactors that influence recurrence risk in primary Clostridioides difficile infection (CDI) are poorly understood, and tools to predict recurrence are lacking. Perturbations in microbial-derived bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis.AimsTo define stool bile acid profiles and microbial bile-metabolising functionality in primary CDI patients, and explore signatures predicting recurrence.MethodsWeekly stool samples were collected from primary CDI patients from the last day of anti-CDI therapy until recurrence, or through eight weeks post-completion otherwise. Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to profile bile acids, and bacterial bile salt hydrolase (BSH) activity was measured to determine primary BA deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in recurrers versus non-recurrers, and assess fecal bile acids as predictive markers for recurrence.ResultsTwenty (36%) out of 56 patients (median age 57, 64% male) recurred, with 80% of recurrence occurring within the first nine days post-antibiotic treatment. Principal component analysis (PCA) of stool bile acid profiles demonstrated clustering of samples by recurrence status and post-treatment time point. Longitudinal fecal bile acid trajectories in non-recurrers showed a recovery of secondary bile acids and their derivatives in non-recurring patients that was not observed in recurrers. BSH activity increased over time amongst patients who did not relapse (β= 0.056; likelihood ratio test p=0.018). A joint longitudinal-survival model identified five stool bile acids with AUROC > 0.73 for prediction of recurrence within nine days post-CDI treatment.ConclusionsGut bile acid metabolism dynamics differ in primary CDI patients between those who develop recurrence versus those who do not. Individual bile acids show promise in primary CDI patients as potential novel biomarkers to predict CDI recurrence.

Background Clostridioides difficile infection (CDI) is the most common hospital acquired infection in the USA, with recurrence rates > 15%. Although primary CDI has been extensively linked to gut microbial dysbiosis, less is known about the factors that promote or mitigate recurrence. Moreover, previous studies have not shown that microbial abundances in the gut measured by 16S rRNA amplicon sequencing alone can accurately predict CDI recurrence. Results We conducted a prospective, longitudinal study of 53 non-immunocompromised participants with primary CDI. Stool sample collection began pre-CDI antibiotic treatment at the time of diagnosis, and continued up to 8 weeks post-antibiotic treatment, with weekly or twice weekly collections. Samples were analyzed using (1) 16S rRNA amplicon sequencing, (2) liquid chromatography/mass-spectrometry metabolomics measuring 1387 annotated metabolites, and (3) short-chain fatty acid profiling. The amplicon sequencing data showed significantly delayed recovery of microbial diversity in recurrent participants, and depletion of key anaerobic taxa at multiple time-points, including Clostridium cluster XIVa and IV taxa. The metabolomic data also showed delayed recovery in recurrent participants, and moreover mapped to pathways suggesting distinct functional abnormalities in the microbiome or host, such as decreased microbial deconjugation activity, lowered levels of endocannabinoids, and elevated markers of host cell damage. Further, using predictive statistical/machine learning models, we demonstrated that the metabolomic data, but not the other data sources, can accurately predict future recurrence at 1 week (AUC 0.77 [0.71, 0.86; 95% interval]) and 2 weeks (AUC 0.77 [0.69, 0.85; 95% interval]) post-treatment for primary CDI. Conclusions The prospective, longitudinal, and multi-omic nature of our CDI recurrence study allowed us to uncover previously unrecognized dynamics in the microbiome and host presaging recurrence, and, in particular, to elucidate changes in the understudied gut metabolome. Moreover, we demonstrated that a small set of metabolites can accurately predict future recurrence. Our findings have implications for development of diagnostic tests and treatments that could ultimately short-circuit the cycle of CDI recurrence, by providing candidate metabolic biomarkers for diagnostics development, as well as offering insights into the complex microbial and metabolic alterations that are protective or permissive for recurrence.

Clostridioides difficile infection occurs when the bacterium produces toxin that causes diarrhea and inflammation of the colon. These guidelines indicate the preferred approach to the management of adults with C. difficile infection and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation process. In instances where the evidence was not appropriate for Grading of Recommendations Assessment, Development, and Evaluation but there was consensus of significant clinical merit, key concept statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not the only, approach to clinical scenarios.

Purpose of review Clostridioides difficile infection (CDI) may complicate the course of ulcerative colitis and Crohn's disease. The clinical presentation of CDI in this population is often atypical, and patients may experience exacerbations of their underlying inflammatory bowel disease (IBD) secondary to C. difficile. In this review, we aim to review the risk factors, diagnosis, and management of CDI in the context of IBD. Recent findings Patients with colonic involvement of their IBD are at higher risk for CDI and colonization may be more common than in the general population. Therefore, CDI is confirmed using a two-step approach to stool testing. Oral vancomycin or fidaxomicin are the preferred agents for nonfulminant disease, and oral metronidazole is no longer recommended as first-line therapy. For all patients with CDI recurrence, fecal microbiota transplant (FMT) should be considered, as this has been shown to be safe and effective. Among those who have worsening of their underlying IBD, retrospective research suggest that outcomes are improved for those who undergo escalation of immunosuppression with appropriate antimicrobial treatment of C. difficile, however prospective data are needed. Summary CDI may complicate the course of IBD, however the presentation may not be typical. Therefore, all patients with worsening gastrointestinal symptoms should be evaluated for both CDI and IBD exacerbation. Providers should consider FMT for all patients with recurrent CDI as well as escalation of immunosuppression for patients who fail to improve with appropriate antimicrobial therapy.

Fecal microbiota transplantation (FMT) emerged as rescue treatment for multiply recurrent Clostridioides difficile infections (rCDIs) nonresponsive to standard therapy. However, estimation of FMT efficacy varies among different protocols and formulations, while placebo-controlled clinical trials have excluded most rCDI patients because of medical comorbidities. This study aimed to determine the safety and effectiveness of capsule FMT (cap-FMT) and colonoscopy FMT (colo-FMT) for rCDI using standardized products in a large, multicenter, prospective, real-world cohort.Clinical outcomes and adverse events after FMT performed for rCDI at 6 sites were captured in a prospective registry. FMT was performed using 1 of 2 standardized formulations of microbiota manufactured by the University of Minnesota Microbiota Therapeutics Program, freeze-dried/encapsulated or frozen-thawed/liquid. The FMT administration route was determined by the treating physician. The rCDI cure rate was assessed at 1 and 2 months. Safety data were collected within the first 72 hours and at 1 and 2 months. Logistic regression was used to investigate factors associated with FMT failure.A total of 301 FMTs were performed in 269 unique patients. Two-thirds were cap-FMT. CDI cure rates were 86% (95% CI, 82%-90%) at 1 month and 81% (95% CI, 75%-86%) at 2 months. There was no difference in the 1-month or 2-month cure rate between cap-FMT and colo-FMT. Cap-FMT recipients were older and less likely to be immunosuppressed or have inflammatory bowel disease. Patient factors of older age and hemodialysis were associated with FMT failure by 2 months on multivariate logistic regression. In addition, post-FMT antibiotic use was associated with FMT failure at 2 months. One serious adverse event was related to colonoscopy (aspiration pneumonia), otherwise no new safety signals were identified.Cap-FMT using freeze-dried capsules has a similar safety and effectiveness profile compared with colo-FMT, without the procedural risks of colonoscopy. Although highly effective overall, patient selection is a key factor to optimizing FMT success.

Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridioides difficile infection (CDI); however, a small percentage of patients fail to achieve cure even after two FMTs. This high-risk cohort remains poorly understood. We performed a multicenter, multinational retrospective review of patients that underwent at least one FMT for a CDI indication at four academic FMT referrals. Patients’ data including CDI, FMT, and FMT variables were assessed. The primary outcome was FMT failure after a second FMT defined as persistent diarrhea and positive laboratory test for C. difficile (PCR or toxin) despite a second FMT within 8 weeks of the first FMT. A multivariable logistic regression model was performed to determine predictors of second FMT failure. A total of 540 patients received at least one FMT during the study period, of which 432 patients had success following the first FMT, 108 had documented failure (25%). Among those who failed the first FMT, 63 patients received a second FMT, of which 36 achieved cure, and 24 had documented failure after the second FMT. Patients that failed the first FMT but did not receive a second FMT and those lost to follow-up were excluded leaving 492 patients included in the analysis. The second FMT failure rate was 4.8% (24/492). Risk factors for second FMT failure identified by multivariable logistic regression included: inpatient status (OR 7.01, 95% CI: 2.37–20.78), the presence of pseudomembranes (OR 3.53, 95% CI: 1.1–11.33), and immunocompromised state (OR 3.56, 95% CI: 1.45–8.72) at the time of first FMT. This study identifies clinically relevant risk factors predictive of failing a second FMT. Clinicians can use these variables to help identify high-risk patients and provide a better-informed consent regarding the possibility of needing multiple FMTs.

Characterize and compare the risk of Clostridioides difficile infection (CDI) and cytomegalovirus colitis (CMVC) after initiation of vedolizumab or anti-tumor necrosis factor (TNF)α agents for ulcerative colitis (UC).Immunosuppression is a risk factor for gastrointestinal infections including CDI and CMVC among patients with UC; however, the risk according to the biological class is poorly understood.A retrospective cohort study of adults with UC involving the initiation of vedolizumab or anti-TNFα agents during June 1, 2014 to December 31, 2020 was conducted at a large academic health system. The primary outcomes for both CDI and CMVC analyses were first CDI or CMVC after biological initiation. The secondary outcome for the CDI analysis was severe CDI (10,000 white blood cells or serum creatinine1.5 mg/dL). Independent variables included demographics and UC history/severity factors. Inverse probability of treatment weighted Cox regression was performed to assess the hazard of CDI by biological group. Due to few outcomes, CMVC was reported descriptively.A total of 805 UC patients initiated vedolizumab (n=195) or anti-TNFα agents (n=610). There were 43 CDIs and 11 severe CDIs over 1436 patient-years. The inverse probability of treatment weighted Cox regression demonstrated no association between CDI and vedolizumab versus anti-TNFα (hazard ratio 0.33, 95% confidence interval 0.05-2.03), but identified a significantly lower hazard of severe CDI for vedolizumab versus anti-TNFα (hazard ratio 0.10, 95% confidence interval 0.01-0.76). There were 5 cases of CMVC, all in the anti-TNFα group.There was a lower adjusted risk of severe CDI but not total CDI associated with vedolizumab. CMVC was not observed after initiating vedolizumab. These findings may provide reassurance regarding the use of vedolizumab when also considering the risk of gastrointestinal infections.

Despite the importance of microbial dysbiosis in human disease, the phenomenon remains poorly understood. We provide the first comprehensive and predictive model of dysbiosis at ecosystem-scale, leveraging our new machine learning method for efficiently inferring compact and interpretable dynamical systems models. Coupling this approach with the most densely temporally sampled interventional study of the microbiome to date, using microbiota from healthy and dysbiotic human donors that we transplanted into mice subjected to antibiotic and dietary interventions, we demonstrate superior predictive performance of our method over state-of-the-art techniques. Moreover, we demonstrate that our approach uncovers intrinsic dynamical properties of dysbiosis driven by destabilizing competitive cycles, in contrast to stabilizing interaction chains in the healthy microbiome, which have implications for restoration of the microbiome to treat disease.

Background Patients with ulcerative colitis (UC) on ustekinumab (UST) therapy may have suboptimal response to standard every 8 week (q8w) dosing. Empiric dose escalation to q4w or q6w is common, but the efficacy of these strategies are unknown in UC. We performed a multicenter cohort study to identify predictors and outcomes of UST dose escalation in UC. Methods This retrospective cohort study included adults initiating UST for UC (ICD-10-CM 51x) at three academic medical centers in the United States 1/1/2016-11/1/2021. Patients with prior colectomy were excluded. Disease activity was assessed using the 9-point Mayo score or simple clinical colitis activity index (SCCAI) in electronic health records. Independent variables included demographics, UC duration, extraintestinal manifestation, medication/substance use history, endoscopic extent/severity, reason for escalation, intravenous (IV) reinduction, dose interval, albumin, C-reactive protein, and bowel frequency. The primary outcome was steroid-free clinical remission (SCCAI/Mayo Results 108 UC patients initiated UST: 91.7% had prior anti-TNF exposure and 57.4% were taking oral steroids (Table 1). 39.6% (40/101 with data) achieved remission 12–16 weeks after induction. 42.6% (46/108) were escalated to q4w (n=33) or q6w (n=13) after median of 95 days (IQR 65–208 days) primarily for no/minimal response to induction (22/46) or loss of response (20/46) (Fig 1A). 55.0% (22/40 with data) achieved remission at 12–16 weeks, 67.5% (27/40) had response, 56.3% (9/16 with data) had endoscopic response (Table 2), and 30.0% (12/40) had treatment failure (Fig 1B). 10.0% (4/40) were hospitalised after median of 80 days and 5.0% (2/40) had adverse events (urinary tract infection and C. difficile infection). After multivariable analysis, lack of response to induction was inversely associated with remission after escalation. Bowel frequency and >2 prior biologics were associated with time to escalation (Table 3). Conclusion UST dose escalation resulted in clinical remission in >50% of UC patients and was more effective in those with loss of response compared to no/minimal response after induction. Prospective studies are needed to identify UC subpopulations that will benefit from various dosing strategies of UST.

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We aimed to describe the real-world treatment experience and corticosteroid utilisation of patients treated with tofacitinib in a US claims database.Patients with a UC diagnosis who initiated tofacitinib, vedolizumab or tumour necrosis factor inhibitor (TNFi) treatment between May 2018 and July 2019 were identified from the Optum Research Database. Demographic and clinical characteristics of patients who initiated tofacitinib, vedolizumab or TNFi were described. Oral corticosteroid use prior to and following tofacitinib initiation was evaluated. Tofacitinib adherence (proportion of days covered) and continuation was assessed for 6 months following initiation. Analyses were descriptive and stratified by prior biologic use (naïve, 1 or ≥ 2; minimum of 12 months prior to tofacitinib initiation).Among patients initiating tofacitinib (N = 225), mean age was 45.6 (SD 16.5) years and 50.2% were female. Of these, 43 (19.1%) patients were biologic-naïve and 182 (80.9%) had prior biologic use (92 [40.9%], 1 prior biologic; 90 [40.0%], ≥ 2 prior biologics). Among patients with 1 prior biologic, 82.6% were previously treated with a TNFi. Among patients with ≥ 2 prior biologics, 54.4% were previously treated with vedolizumab and a TNFi, 16.7% with two TNFi and 28.9% with ≥ 3 prior biologics. In the 6 months prior to tofacitinib initiation, 65.8% of patients had received oral corticosteroids (74.4%, 60.9% and 66.7% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively). The proportion of patients with ongoing oral corticosteroid use 3-6 months after tofacitinib initiation decreased to 13.3% (9.3%, 18.5% and 10.0% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively), and 19.6% of patients discontinued oral corticosteroid use during the 6 months after tofacitinib initiation. Overall, tofacitinib adherence, as determined by the mean proportion of days covered during the 6-month follow-up, was 0.7 (median 0.8). During the 6-month follow-up, 84.9% of patients continued tofacitinib.Among patients with UC initiating tofacitinib, the majority had prior biologic use. Tofacitinib adherence was high, discontinuation was low and oral corticosteroid utilisation decreased irrespective of prior biologic use. Further research with longer follow-up and a larger sample size is required.

Ustekinumab has been shown to be effective for the treatment of ulcerative colitis (UC); however, >40% of patients have suboptimal clinical response after induction and maintenance dosing every 8 weeks.1,2 The best management approach for these patients is unclear. Many undergo empiric dose intensification to every 4 weeks or every 6 weeks, a nonstandardized decision because of limited data supporting therapeutic drug monitoring of ustekinumab.3 In Crohn's disease, approximately 50% of patients undergo ustekinumab dose intensification, which seems to be effective based on prior work from our group and others.4-8 However, similar data in UC are lacking. In this real-world multicenter cohort study, we sought to identify predictors and outcomes of ustekinumab dose intensification in UC.