Severe Ulcerative Colitis Patients Research Articles

The efficacy and safety of infliximab and calcineurin inhibitors in steroid-refractory UC patients: A meta-analysis.

Background:Infliximab (IFX) and calcineurin inhibitors (cyclosporine [CYS] and tacrolimus [TAC]) were considered as rescue therapy in steroid-refractory ulcerative colitis (UC). The objective of our study was to perform a meta-analysis evaluating the short-term and long-term efficacy and safety of IFX and calcineurin inhibitors in steroid-refractory UC.Methods:We systematically searched the databases from inception to September 2020 that evaluated IFX, CYS, and TAC in steroid-refractory UC. The primary outcome was the response rates, remission rates, mucosal healing rates, and colectomy rates after therapy initiation. The secondary outcomes were the rates of adverse events (AE), serious adverse events (SAE), and mortality. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated.Results:Nineteen studies comprising 1323 Acute severe ulcerative colitis (ASUC) patients were included in the meta-analysis. Among the non-randomized studies, a significantly higher therapeutic response rate was seen with IFX treatment, with a pooled OR of 3.15 (95% CI 2.26–4.40). Among non-randomized studies, IFX was associated with a significantly lower first-year OR (0.46 [95% CI 0.27–0.79]), second-year (OR 0.53 [95% CI 0.28–0.97]), third-year (OR 0.43 [95% CI 0.24–0.75]) colectomy rate. But the randomized controlled trials (RCTs) did not suggest any difference between IFX and CYS as rescue therapies for steroid-refractory UC. There were no significant differences among IFX, CYS, and TAC in the rates of AE, SAE, or mortality.Conclusion:Our meta-analysis suggested a better treatment response rate and lower risk of colectomy in the first, second and third year, with IFX, compared with CYS in steroid-refractory UC patients. There was no significant difference among IFX and calcineurin inhibitors in AE, SAE, and mortality.

Real-world experience with tofacitinib in ulcerative colitis: a systematic review and meta-analysis.

Background and aims:Tofacitinib is a Janus kinase inhibitor (JAKi) recently approved for the treatment of moderate to severe ulcerative colitis (UC) based on robust efficacy and safety data derived from OCTAVE clinical trials. Evidence on the outcomes of tofacitinib therapy in real-world UC patients is needed, as a number of these patients would be deemed ineligible for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe UC patients.Methods:We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30 May 2018 and 24 January 2021. Pooled induction (8–14 weeks) and maintenance (16–26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models.Results:Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-tumour necrosis factor (TNF) and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% confidence interval, 41–60%) and 37% (26–45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31–50%) and 29% (23–36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%).Conclusion:Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials.

Using Dose-Effect Relationship for Optimising Systemic Corticosteroid Dosage in Treatment of Inflammatory Bowel Diseases

Aim.Estimation of an optimal corticosteroid (CS, prednisone) dosage for the remission induction in patients with ulcerative colitis (UC) and Crohn’s disease (CD) based on the construction of a dose-effect relationship during the first and second courses of therapy.Materials and methods.The study included 86 patients with moderate to severe active disease (61 with UC and 25 with CD) aged 18 to 65 years. To induce remission, all patients had the first course of prednisone at a starting dose of 30 to 60 mg/day, with a subsequent reduction. Prednisone was continued in a repeat course in 28 patients. The effect was evaluated past two weeks and at a time of complete withdrawal of prednisone using the generally accepted clinical response and remission criteria. The dose-effect relationship for prednisone was constructed using an original method. The method realises an adequate statistical transformation of primary clinical data in form of a quantitative expression of factual doses and registered alternative responses established with endpoint criteria into a visual efficacy function graph suitable for downstream analyses. The mean at each point was estimated with the regression kernel scoring method. The mean confidence intervals and significance values were estimated with the Student’st-test.Results.The dose-effect relationship constructed upon completion of the first prednisone course is a graph showing the plateau point of the efficacy function as a statistical measure of character saturation and a clinical measure of the highest expected drug effect. This graph is referred to as the optimal clinically effective dose (OCED). The first induction prednisone course had the OCED estimates of 50.70 ± 0.65 (49.41÷51.98) mg (p= 0.05). A highest expected effect for this dose was obtained in the interval of 82.21 ± 8.23 (66.08÷98.33)% (p= 0.05). The repeat prednisone course had OCED values of 51.43 ± 1.55 (48.24÷54.61) mg (p= 0.05), with the expected effect of 40.02 ± 12.86 (13.59÷66.45)% (p= 0.05).Conclusion.In medium to severe UC and CD patients, the first induction prednisone course had OCED estimates of 50.70 ± 0.65 mg/day prescribed at the onset of therapy. The highest effect at this dose was 82%, and 18% of the patients did not respond to the prednisone treatment, accordingly. The repeat CS treatment had the same OCED values of 51.43 ± 1.55 mg/day, but a 42% lower expected effect compared to the first course. The effect did not exceed 40% suggesting its inadequacy in repeat CS treatments in this category of patients.

P047 Awareness and Impact of Recent AGA Guideline Changes for Moderate to Severe Ulcerative Colitis Patients.

BACKGROUND: In January 2020, the American Gastroenterological Association (AGA) released several guideline changes related to the treatment of moderate to severe ulcerative colitis (UC) patients. One of these changes recommended prescribing infliximab or vedolizumab rather than adalimumab for induction of remission in adults with moderate to severe UC who are new to biologic therapy. A second change recommended prescribing ustekinumab or tofacitinib, rather than vedolizumab or adalimumab for induction of remission in UC patients who have been exposed to infliximab and who were not responsive. This research sought to demonstrate the impact that awareness of guideline changes has on use of therapies impacted by each guideline change. METHODS: An independent market analytics firm collaborated with US gastroenterologists (n = 112) to conduct an analysis on the US inflammatory bowel disease (IBD) market. Data collected from the participating gastroenterologists include basic demographics, prescribing behavior, and attitudinal survey responses. Data were collected in April 2020. Responding gastroenterologists were required to predominantly treat adult patients, have at least 50 IBD patients under their management, and spend at least half of their professional time in clinical practice. RESULTS: 66% of gastroenterologists reported awareness of the guideline change recommending the prescribing of infliximab or vedolizumab rather than adalimumab for induction of remission in adult, moderate to severe ulcerative colitis patients who are new to biologic therapy. Using a five point scale, 51% of physicians indicated the guideline change would have some impact (four out of five rating) or a large impact (five out of five rating) on their prescribing of vedolizumab in moderate to severe ulcerative colitis patients. 54% of gastroenterologists reported awareness of the guideline change recommending the prescribing of ustekinumab or tofacitinib rather than vedolizumab or adalimumab for induction of remission in adult, moderate to severe ulcerative colitis patients who have been exposed to infliximab and who were not responsive. Using a five point scale, 63% of physicians indicated the guideline change would have some impact (four out of five rating) or a large impact (five out of five rating) on their prescribing of ustekinumab in these patients, while 32% of gastroenterologists indicated a similar response for their prescribing of tofacitinib in these patients. CONCLUSION: A majority of gastroenterologists have awareness of the AGA guideline changes relative to adult, moderate to severe ulcerative colitis patients new to biologics and that awareness has a positive effect on prescribing of vedolizumab in these patients. Approximately one-half of gastroenterologists are aware of the AGA guideline change relative to adult moderate to severe ulcerative colitis patients who have been exposed to infliximab and who were not responsive. This awareness also had a positive effect on prescribing of ustekinumab, and to a lesser extent, tofacitinib, in these patients.

The Importance of Sarcopenia as a Prognostic Marker for Clinical Course and Postoperative Outcomes in Acute Severe Ulcerative Colitis Patients

Background: Acute severe ulcerative colitis (ASUC) is a life-threatening condition, which needs timely referral for first-line and second-line therapy. Although various clinical parameters for predicting response to intravenous steroid (IVS), rescue medical therapy, or colectomy and for evaluating postoperative outcomes already exist, there is few data concerning the role of sarcopenia in ASUC. The relationship between sarcopenia and clinical course in ASUC was evaluated in this study. Methods: This cohort study included ASUC patients with abdominal CT scan. Quantification of body composition was assessed. Multivariable regression was performed to find out a practical predictive index for clinical course and colectomy of ASUC. Findings: Of 233 included patients, 151 showed nil response to IVS therapy, among whom 32 received surgery without rescue medical therapy. 50 patients suffered colectomy after medical rescue therapy failure during one-year follow-up. Of 82 surgical patients, 42 recovered eventfully. Multivariable regression analysis showed sarcopenia (OR=2.962; 95% CI, 1.532-5.726; p=0.001) remained an independent risk factor for IVS failure, subcutaneous fat areas (OR=0.985; 95% CI, 0.970-1.000; p=0.046) was an independent predictor for colectomy during one year after second-line medical failure, and sarcopenia (OR, 4.157; 95% CI, 1.364-12.667; p=0.012) remained an independent risk factor for postoperative complications. During follow-up, patients with colectomy after first-line medical had higher health-related quality of life and sarcopenic patients suffered the pouchitis more frequently. Interpretation: The sarcopenia was superior to other common indicators in predicting clinical course and postoperative outcomes in ASUC. Funding Statement: This work was supported by National Natural Science Foundation of China (grant number 81800474). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: This cohort study was approved by the Ethics Committee of Medical School of Zhejiang University, China.

IgA, albumin, and eosinopenia as early indicators of cytomegalovirus infection in patients with acute ulcerative colitis

BackgroundCytomegalovirus (CMV) infection can significantly complicate and worsen the condition of acute severe ulcerative colitis (UC) patients. We aimed to explore the predictive risk factors to prevent and identify CMV infection at an early stage in acute UC patients.MethodsA total of 115 moderate-to-severe active UC patients from 17 hospitals throughout China were enrolled. Active CMV infection was diagnosed by one of the following: CMV pp65 antigens, CMV IgM antibodies or CMV DNA. We identified the independent risk factors by multivariate analyses.ResultsA total of 64 of 115 active UC patients had active CMV infection. Compared to the non-CMV-infected patients, the CMV-infected patients had a tendency to be male and to exhibit abdominal pain; fever; oral ulcers; eosinopenia; low albumin, immunoglobulin (Ig) A, IgM, and IgG levels; increased high-sensitivity C-reactive protein (hsCRP) levels; hyponatremia; pancolonic lesions; initial onset type; severe activity; and glucocorticoid (high-dose) and immunosuppressive agent use (P < 0.05). In further multivariate analyses, the use of high-dose glucocorticoids (OR 13.55, 95% CI 2.49–73.61, P < 0.01) and immunosuppressive agents (OR 11.23, 95% CI 1.05–119.99, P = 0.04) were independent risk factors for CMV infection. A decrease eosinophil and albumin levels were risk factors for CMV infection. With every 0.1*10^9/L decrease in the peripheral blood eosinophil level or 1 g/L decrease in the serum albumin level, the risk for CMV infection in UC patients increased by 5.21-fold (1/0.192) or 1.19-fold (1/0.839), respectively.ConclusionsHigh-dose glucocorticoid and immunosuppressive agent treatment significantly increase the risk of CMV infection, and correcting eosinopenia and low albumin levels may help prevent CMV infection in UC patients.

The diagnostic role and clinical association of serum proteinase 3 anti-neutrophil cytoplasmic antibodies in Chinese patients with inflammatory bowel disease

Background and aim: Accurate differentiation of patients with ulcerative colitis (UC) or Crohn’s disease (CD) is important for appropriate therapy and prognosis. This study was designed to explore the utility of proteinase 3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA) in the diagnosis of Chinese patients with inflammatory bowel disease (IBD).Methods: Blood samples were collected from 216 Chinese patients, including 175 IBD and 41 colorectal polyps (disease control). Clinical characteristics were extracted from electronic medical records.Results: Serum PR3-ANCA were increased in UC patients compared to those with CD or colorectal polyps (p < .0001). PR3-ANCA was negative in colorectal polyps and there was no significant difference between CD and colorectal polyps (p > .05). Using the cut-off value of 20 chemiluminescent units (CU) provided by manufacturer, the positive rate of PR3-ANCA was higher in UC than CD (41.7% vs. 1.1%; p < .0001). Receiver operating characteristic (ROC) analysis demonstrated an area under the curve (AUC) of 0.89 (95% CI: 0.84–0.95; p < .0001) for differentiating UC from CD and suggested an optimized cutoff of 7.3 CU which improved sensitivity from 41.7% to 57.1%, while maintaining a specificity of 98.9%. PR3-ANCA in severe UC patients were higher than those with moderate UC (p < .05), no difference was found between those in remission or with mild or moderate activity (p > .05).Conclusions: Serum PR3-ANCA is a potentially useful clinical biomarker in Chinese patients with IBD. A modified cut-off value of 7.3 CU improves the performance for distinguishing UC from CD.

TRPV Subfamily (TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6) Gene and Protein Expression in Patients with Ulcerative Colitis.

Introduction TRPVs are a group of receptors with a channel activity predominantly permeable to Ca2+. This subfamily is involved in the development of gastrointestinal diseases such as ulcerative colitis (UC). The aim of the study was to characterize the gene and protein expression of the TRPV subfamily in UC patients and controls. Methods We determined by quantitative PCR the gene expression of TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6 in 45 UC patients (29 active UC and 16 remission UC) and 26 noninflamed controls. Protein expression was evaluated in 5 μm thick sections of formalin-fixed, paraffin-embedded tissue from 5 customized severe active UC patients and 5 control surgical specimens. Results TRPV2 gene expression was increased in the control group compared with active UC and remission patients (P = 0.002 and P = 0.05, respectively). TRPV3 gene expression was significantly higher in controls than in active UC patients (P = 0.002). The gene expression of TRPV4 was significantly higher in colonic tissue from patients with remission UC compared with active UC patients (P = 0.05) and controls (P = 0.005). TRPV5 had significantly higher mRNA levels in a control group compared with active UC patients (P = 0.02). The gene expression of TRPV6 was significantly higher in the colonic tissue from patients with active UC compared with the control group (P = 0.05). The protein expression of TRPV2 was upregulated in the mucosa and submucosa from the controls compared with the UC patients (P ≤ 0.003). The protein expression of TRPV3 and TRPV4 was upregulated in all intestinal layers from the controls compared with the UC patients (P < 0.001). TRPV5 was upregulated in the submucosa and serosa from the controls vs. UC patients (P < 0.001). TRPV6 was upregulated in all intestinal layers from the UC patients vs. controls (P ≤ 0.001). Conclusion The TRPV subfamily clearly showed a differential expression in the UC patients compared with the controls, suggesting their role in the pathophysiology of UC.

P055 MARKOV CHAIN ECONOMIC IMPACT MODEL FOR ANTI-TNF NON-RESPONSE STRATIFICATION OF PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS

Abstract Objective The annual cost of ulcerative colitis (UC) in the US is estimated to be as high as $14.9 billion, of which therapeutics account for up to 45%. The mean annual drug cost per patient with moderate to severe UC is $28,586. However, only 49% of patients achieve endoscopic healing on their first anti-tumor necrosis factor (anti-TNF) therapy and up to half of UC patients on biologics discontinue therapy within 12 months of initiation which leads to high rates of hospitalization and surgery. We performed a health care payer budget impact analysis to assess the influence of a precision medicine RNA-based classifier (PrismUC) that predicts, at baseline, anti-TNF non-response in patients with moderate to severe UC. Methods We developed a 12-month budget impact model for a 1-million-member health plan by analyzing peer-reviewed literature of treatment patterns in commercial and Medicare populations moderate to severe UC patients. Inputs included drug and medical costs, UC prevalence, biologic assignment patterns, therapy response rates, therapy persistence, therapy cycling, endoscopic healing rates, and risk of surgery. Drug and medical costs were obtained from published literature. A Markov model was created to estimate indirect effects of treatment efficacy, timing and cost of disease progression in subjects identified as anti-TNF non-responders (patients who fail to achieve endoscopic healing). Non-responders were assigned either to an alternative first-line therapy (vedolizumab) or to the standard of care (SOC) as determined by clinician judgments and payer formularies. The SOC included cycling patients through various biologics such as anti-TNF, vedolizumab, tofacitinib and ustekinumab. The cost of SOC was compared that of implementing a classifier to stratify patients by primary non-response to anti-TNF. Final cost savings included the cost of drugs, hospitalizations, and surgeries. Results Introducing a classifier that identifies anti-TNF non-responder UC patients to a 1-million-member health plan resulted in annual cost savings ranging from $6.8 to $9.6 million total (Table 1) within a 12-month period with and $9.0 to $12.7 thousand per patient (Table 2), depending on classifier performance metrics. Conclusion The PrismUC precision medicine classifier test that identifies non-responders to anti-TNF therapy will provide significant economic savings to payers by decreasing expenditures on unnecessary drugs and shortening times to endoscopic healing. These savings provide an economic incentive for payers to proactively engage with diagnostics manufacturers and encourage development of such tools to improve care management. A subsequent classifier that predicts response to therapies with alternative mechanisms of action is in development and expected to yield even higher cost savings.

P276 Reactivation of Epstein–Barr virus and cytomegalovirus behaves differently in pathophysiology of ulcerative colitis

Abstract Background Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) are members of the herpesvirus family. CMV reactivation is often complicated with ulcerative colitis (UC) and is known as one of exacerbation factors. However, the association between EBV reactivation and pathophysiology of UC is still unclear. Methods This study enrolled 116 active UC patients who received colonoscopy between January 2005 and January 2019 in Kyoto University Hospital. 244 biopsy specimens were obtained from inflamed colonic mucosa to assess EVB and CMV reactivation. Viral loads of EBV and CMV in inflamed mucosa were measured by real-time PCR assay. The reactivation of those viruses was defined as DNA quantity more than 10 copies/μg DNA. Clinical severity was assessed by Lichtiger index and defined as follow: 4–8 as mild, 9–12 as moderate, and more than 12 as severe. Endoscopic severity was assessed by Mayo endoscopic score. We examined the correlation between the positivity of each viral reactivation and patients’ characteristics or prognosis of UC. Results (1) Median age, Lichtiger score and Mayo endoscopic score at the time to assess the viral reactivations were 36 years-old, 8, and 3, respectively. (2) EBV and CMV reactivation were observed in 127 samples (52.0%) and 73 samples (29.9%), respectively. There was no correlation between EBV and CMV viral load (correlation coefficient 0.19), although a significant correlation between those viral reactivations was observed in active colonic mucosa of UC patients (p = 0.002). (3) The proportion of EBV reactivation was higher in both clinically and endoscopically severe UC patients compared with those with mild activity. On the other hands, there was no association between CMV reactivation and clinical or endoscopic severity. (4) Multivariate analysis indicated risk factors for EBV reactivation as receiving anti-TNF-α antibodies (odds ratio [OR] 4.2) or calcineurin inhibitors (OR 3.5), and CMV reactivation (OR 2.1), respectively. (5) Multivariate analysis also indicated risks for CMV reactivation as steroid-refractory (OR 4.7) and EBV reactivation (OR 2.0). (6) EBV and CMV reactivation did not affect clinical outcomes including the requirement of colectomy or intensification of immunosuppressive treatments and the incidence of colitis-associated cancer, dysplasia and lymphoproliferative disease. Conclusion Reactivation of EBV or CMV may behave differently in pathophysiology of UC. Further studies are required to clarify the role of EBV reactivation on colonic inflammation in UC patients.

P565 Efficacy and safety of long-term treatment with ustekinumab in moderate–severe ulcerative colitis patients with delayed response to ustekinumab induction: Results from UNIFI 2-year long-term extension

Abstract Background Ustekinumab (UST) has been shown to induce and maintain clinical response and remission in moderate–severe UC patients in the UNIFI study. In the UNIFI maintenance study, the primary randomised population consisted of patients who were in clinical response 8weeks after UST induction treatment. Patients who had a delayed response to induction were also eligible for the maintenance study but were not included in the randomised analysis set. Here, we present the efficacy and safety of UST maintenance among delayed responders who were treated in the UNIFI long-term extension(LTE). Methods UNIFI was a single protocol of induction and randomised withdrawal maintenance studies in patients with moderate–severe UC who failed conventional or biologic therapy(including TNF antagonists and/or vedolizumab). Delayed responders were patients who were not in clinical response to UST IV induction at Week8 but achieved response at Week16 following a single UST90mg SC dose at Week8. These patients entered the maintenance study and continued to receive UST90mg SC q8w. Patients who completed Week44 evaluations were eligible to enter LTE continuing to receive UST90mg SC q8w. Efficacy in delayed responders to UST(who were treated in LTE) was evaluated over time through Week92 and safety through Week96. Results 116 delayed responders to UST induction were treated in the LTE, including 58 who had previously failed biologic therapy and 58 who had not failed biologic therapy, 54 of whom were bio-naïve. Symptomatic remission(defined as stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0) rates in delayed responders to UST induction increased from maintenance baseline to Weeks 44 and 92 (Table 1). Similar trends were seen within the biologic failure subgroups; although, rates among patients who had not failed biologics (primarily bio-naïve) were greater than those of patients who had failed biologics. Among the 79.3% (n = 92/116) of delayed responders to UST in symptomatic remission at Week 92, 94.6% (n = 87/92) were corticosteroid free. Safety data for randomised and non-randomised patients treated in UNIFI LTE is in Table2. The safety profile for UST in delayed responders was generally similar to that observed among patients randomised to UST; no new safety signals were observed. Conclusion Delayed responders to UST treatment maintained symptomatic remission through Week 92 with UST90mg SC q8w and the majority did so in the absence of corticosteroids.

A new treatment for ulcerative colitis: Intracolonic Bifidobacterium and xyloglucan application

Ulcerative colitis (UC) pathogenesis includes the altered gut microbiota, environmental factors, and human immune and genetic predisposition. Recently, its association with reduced bifidobacteria quantity in the microbiota is reported. Xyloglucan, a plant-based prebiotic oligosaccharide, causes increase in bifidobacteria quantity. In this article, we share the results of our UC cases treated by intracolonic single-dose administration of Bifidobacterium animalis subsp. lactis and xyloglucan combination. Intracolonic single-dose administration of 200 billion colony-forming units (CFUs) of B. animalis subsp. lactis and 4 g of xyloglucan combination was administrated to 10 severe UC patients, who were either unresponsive or had inadequate response to treatment. All patients continued treatment after the procedure. Treatment responses were evaluated by colonoscopic, laboratory, and clinical examination after 6 weeks. Intracolonic single-dose administration of B. animalis subsp. lactis and xyloglucan was found effective in the mucosal healing and resolution of colonic symptoms in UC patients. Intracolonic administration of B. animalis subsp. lactis and xyloglucan in UC is a new single-strain and strain-specific prebiotic combination method. It is easy to apply and has no observable side effect. Its effectiveness on mucosal healing could be attributed to the enhancement of non-stimulatory status and biodiversity in colonic mucosa. Nonetheless, it is still necessary to develop diagnostic strategies to determine the patients to whom this method would be the most applicable.

Comparison of the Intestinal Drug Permeation and Accumulation Between Normal Human Intestinal Tissues and Human Intestinal Tissues With Ulcerative Colitis

The purpose of this study was to examine drug absorption profile utilizing human intestinal tissues from ulcerative colitis (UC) patients and to compare with normal tissues from intestinal cancer patients. Human intestinal tissues from UC and cancer patients mounted in a mini-Ussing chamber were used to evaluate the permeation of drugs, including FD-4, a very low permeable marker, rebamipide, a low permeable marker, and metoprolol, a high permeable marker. The transport index, an index of sum of permeated and tissue-accumulated molecules, of the model drugs was in accordance with their absorption rank order, and was almost kept constant irrespective of autopsy grade based on tissue fibrosis. On the other hand, UC tissues of grade 2 showed the decreased Xcorr, an index of permeated amount of molecules and increased Tcorr, an index of tissue-accumulated molecules for every tested compound.Our finding of the transport characteristics in intestinal tissues of severe UC patients in mini-Ussing chamber system demonstrated that autopsy grade of UC patients did not drastically change membrane permeability of the tested compounds. Furthermore, it was suggested that morphological changes of intestinal tissues caused by fibrosis led to limited permeation and subsequently increased accumulation with little change of total absorption.

Comparison of medium to long-term outcomes of acute severe ulcerative colitis patients receiving accelerated and standard infliximab induction

IntroductionAccelerated dose infliximab (IFX) induction is associated with reduced short-term colectomy rate in acute severe ulcerative colitis (ASUC). Data on medium/long-term outcomes of this strategy are limited.AimsEvaluate medium/long-term outcomes in...

678 Efficacy of Upadacitinib as an Induction Therapy in Severe and Refractory Ulcerative Colitis: Sub-Group Analysis of the Phase 2b Study U-ACHIEVE

INTRODUCTION: An unmet need exists to find effective therapy in more severe ulcerative colitis (UC) patients, especially those who have failed multiple therapies. The efficacy and safety of upadacitinib, a selective Janus Kinase 1 inhibitor, has been assessed in an 8-week double-blind, placebo-controlled, dose-ranging, phase 2b induction study in adult patients with moderately-to-severely active UC (U-ACHIEVE).1,2 METHODS: In U-ACHIEVE, adult patients with moderately-to-severely active UC as determined by the Adapted Mayo Score (5-9 points and centrally-read endoscopy subscore 2-3) were randomized to receive extended-release upadacitinib 7.5, 15, 30, 45 mg once daily (QD) or placebo for 8 weeks. In the current sub-analysis, the efficacy of upadacitinib in more severe and/or more refractory patient populations was assessed. Patients who at baseline had failed ≥2 prior biologic agents, had pancolitis, and/or an Adapted Mayo score &gt;7, were included. Pairwise comparisons between upadacitinib doses and placebo for the primary endpoint, clinical remission per Adapted Mayo Score at Week 8 (defined as stool frequency subscore ≤1, rectal bleeding subscore = 0, and endoscopic subscore ≤1) and secondary endpoints were conducted using the Fisher's Exact test and no multiplicity adjustments were applied. Non-responder imputation was utilized for missing values. RESULTS: At baseline, 142 (56.8% of the total study population) patients had failed ≥2 prior biologics, 135 (54.0%) patients had pancolitis, and 90 (36.0%) patients had an Adapted Mayo score &gt;7. The proportions of patients achieving endoscopic improvement, clinical response per Adapted Mayo score, and clinical response per Partial Mayo score were significantly higher (nominal P-value &lt; 0.05) with upadacitinib doses ≥30 mg QD versus the placebo group in patients who failed ≥2 biologics or had pancolitis at baseline (Table 1). Trends of higher proportions of patients achieving clinical remission per Adapted Mayo score, endoscopic improvement, clinical response per Adapted Mayo score, and clinical response per Partial Mayo score were observed with all upadacitinib groups versus placebo in all the sub-analyses. CONCLUSION: In this dose-ranging induction study, upadacitinib demonstrated greater efficacy compared to placebo with dose response in the more severe and refractory population; significantly greater efficacy was demonstrated with upadacitinib at doses ≥30 mg QD for most of the endpoints evaluated.

Infliximab induction regimens in steroid-refractory acute severe colitis: a multicentre retrospective cohort study with propensity score analysis.

Accelerated induction regimens of infliximab have been proposed to improve response rates in patients with steroid-refractory acute severe colitis. To determine the differences in outcome for acute severe ulcerative colitis between accelerated and standard-dose infliximab METHODS: We collected data on hospitalised patients receiving differing regimens of rescue therapy for steroid-refractory acute severe ulcerative colitis. Our primary outcome was 30-day colectomy rate. Secondary outcomes were colectomy within index admission, and at 90days and 12months. We used propensity score analysis with optimal calliper matching using high risk covariates defined a priori to reduce potential provider selection bias. We included 131 patients receiving infliximab rescue therapy; 102 received standard induction and 29 received accelerated induction. In the unmatched cohort, there was no difference by type of induction in the 30-day colectomy rates (18% vs 20%, P=.45), colectomy during index admission (13% vs 20%, P=.26) or overall colectomy (20% vs 24%, P=.38). In the propensity score-matched cohort of 52 patients, 30-day colectomy (57% vs 27%, P=.048) and index admission colectomy (53% vs 23%, P=.045) rates were higher in those receiving standard induction compared to accelerated induction but there was no difference in overall colectomy rates (57% vs 31%, P=.09). There was no significant difference in length of stay or in complication and infection rates. In a propensity score-matched cohort, steroid-refractory acute severe ulcerative colitis patients, short-term, but not long-term, colectomy rates appear to be lower in those receiving an accelerated induction regimen.

Sonographic Assessment in Severe Ulcerative Colitis Patients Admitted for Intravenous Corticosteroids and Eligible for Infliximab Rescue Therapy; a Prospective Clinician-blinded Observational Study Protocol.

Sonographic Assessment in Severe Ulcerative Colitis Patients Admitted for Intravenous Corticosteroids and Eligible for Infliximab Rescue Therapy; a Prospective Clinician-blinded Observational Study Protocol.

Tacrolimus Therapy in Steroid-Refractory Ulcerative Colitis: A Review.

Inflammatory bowel diseases are known for a chronic inflammatory process of the gastrointestinal tract and include Crohn's disease and ulcerative colitis (UC). Patients who are dependent on or resistant to corticosteroids account for about 20% of severe UC patients. Tacrolimus is a calcineurin inhibitor that has recently been used in the treatment of steroid-refractory ulcerative colitis. Tacrolimus has been demonstrated to have remarkable therapeutic efficacy in UC patients, without increased risk of severe adverse effects such as induction of remission and maintenance therapy. This article reviews the mechanism of action, pharmacogenetics, efficacy, and safety of tacrolimus for patients with steroid-refractory ulcerative colitis.

IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease.

It remains unknown what causes inflammatory bowel disease (IBD), including signaling networks perpetuating chronic gastrointestinal inflammation in Crohn's disease (CD) and ulcerative colitis (UC), in humans. According to an analysis of up to 500 patients with IBD and 100 controls, we report that key transcripts of the IL-7 receptor (IL-7R) pathway are accumulated in inflamed colon tissues of severe CD and UC patients not responding to either immunosuppressive/corticosteroid, anti-TNF, or anti-α4β7 therapies. High expression of both IL7R and IL-7R signaling signature in the colon before treatment is strongly associated with nonresponsiveness to anti-TNF therapy. While in mice IL-7 is known to play a role in systemic inflammation, we found that in humans IL-7 also controlled α4β7 integrin expression and imprinted gut-homing specificity on T cells. IL-7R blockade reduced human T cell homing to the gut and colonic inflammation in vivo in humanized mouse models, and altered effector T cells in colon explants from UC patients grown ex vivo. Our findings show that failure of current treatments for CD and UC is strongly associated with an overexpressed IL-7R signaling pathway and point to IL-7R as a relevant therapeutic target and potential biomarker to fill an unmet need in clinical IBD detection and treatment.

Protective effect of TSLP and IL-33 cytokines in ulcerative colitis

PurposeInflammatory bowel disease (IBD) primarily includes ulcerative colitis (UC) and Crohn’s disease (CD). Thymic stromal lymphopoietin (TSLP) is a cytokine produced by intestinal epithelial cells (IECs) with immunomodulatory properties that plays an important role in the development of regulatory T cell (Treg) responses and tolerance in the gut. On the other hand, IL-33 has been considered as a cytokine with two different properties, inflammatory and anti-inflammatory functions, the latter may play a protective role against chronic intestinal inflammation. In the present study, we investigated the relative gene expression levels of TSLP and IL-33 molecules in ulcerative colitis.MethodsPatients with clinical symptoms of colitis undergoing a routine diagnostic colonoscopy were included in this study. Biopsy specimens were collected and divided into two parts. One part was fixed and processed for routine histopathological examinations and the other part was stored for RNA extraction. TSLP and IL-33 gene expression were determined using the SYBR Green qRT-PCR.ResultsThe expression level of TSLP and IL-33 were significantly lower in UC patients compared with the control group. Moreover, the expressions of these cytokines were more down-regulated in severe UC patients compared with mild and moderate ones and the control group. We also showed a positive correlation between low expression of TSLP and IL-33 and the severity of UC disease.ConclusionsIn this study, we showed decreased mRNA expression levels of TSLP and IL-33 in UC patients and also a negative correlation between expression of TSLP and IL-33 and severity of UC disease.