Modified-Release Phosphatidylcholine (LT-02) for Ulcerative Colitis: Two Double-Blind, Randomized, Placebo-Controlled Trials.

BACKGROUND & AIMS: The aim of this study was to evaluate the efficacy of LT-02, a novel modified-release phosphatidylcholine (PC) formulation, for induction and maintenance of remission in patients with mild to moderate ulcerative colitis (UC) and inadequate response to mesalamine. METHODS: LT-02 was evaluated in a multicenter double-blind, randomized, placebo-controlled study comprising a 12-week induction trial (PCG-2), followed by a 48-week maintenance trial (PCG-4). In PCG-2, patients were randomized 1:1:1 to treatment with 0.8 g LT-02 4 times daily (QID), 1.6 g LT-02 twice daily (BID), or placebo, respectively. All patients continued to take a standard dose of oral mesalamine (≥2.4 g/day). The primary end point in PCG-2 was deep remission. Patients achieving remission at week 12 were randomly assigned 2:1:1 to 1.6 g LT-02 BID, placebo, or 500 mg mesalamine (3 times daily), respectively, in PCG-4; the primary end point was remission at 48 weeks. RESULTS: PCG-2 was terminated early for futility after a prespecified interim analysis; 466 patients (of 762 planned) were randomized. There was no statistically significant difference in deep remission at week 12 (placebo, 13.5%; LT-02 BID, 14.2%; LT-02 QID, 9.7%). In PCG-4, 150 patients (of approximately 400 planned) were randomized. There was no statistically significant difference in remission rates at week 48 (LT-02 BID, 49.3%; mesalamine, 50.0%; placebo, 43.2%). LT-02 was safe. CONCLUSIONS: Despite prior evidence of beneficial effects of PC in phase 2 trials, our induction study with LT-02 in patients with mild to moderate UC was terminated prematurely for futility. Signals of efficacy in maintenance therapy require confirmation in an adequately powered maintenance trial. LT-02 was safe and well-tolerated. CLINICALTRIALS: gov: NCT02280629, NCT02142725.

Induction Efficacy of Upadacitinib in Therapy-Refractory Crohn's Disease: A Retrospective Case Series.

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Achieving clinical and endoscopic remission is the main therapeutic goal.1 Despite available treatment options, some patients present with treatment-refractory disease to approved therapies.2 Randomized clinical trials enable a standardized evaluation of drugs with new modes of action. However, eligibility criteria are strict excluding those with ostomy or failures to other medication leaving a considerable proportion of patients noneligible.3.

[Use of subcutaneous Vedolizumab: A position paper issued by the Inflammatory Bowel Disease Working Group of the Austrian Society of Gastroenterology and Hepatology (ÖGGH)]. / Positionspapier der Arbeitsgruppe Chronisch Entzündliche Darmerkrankungen der ÖGGH zum Einsatz von Vedolizumab subkutan.

The humanized monoclonal anti-α4ß7-integrin-antibody vedolizumab is one of several biologic therapeutic options in moderate-to-severe ulcerative colitis and Crohn's disease. Within the VISIBLE trial program, a novel subcutaneous application route was evaluated in addition to the already established intravenous form. In this position statement, the working group "Inflammatory Bowel Diseases" of the Austrian Society for Gastroenterology and Hepatology (OEGGH) summarizes the evidence regarding the subcutaneous application of vedolizumab. This work supplements a position paper on the value of vedolizumab as a first-line biologic that has already been published and offers useful recommendations for clinical practice.

Deep Remission at 1 Year Prevents Progression of Early Crohn's Disease.

BACKGROUND & AIMS: We investigated the effects of inducing deep remission in patients with early Crohn's disease (CD). METHODS: We collected follow-up data from 122 patients (mean age, 31.2 ± 11.3 y) with early, moderate to severe CD (median duration, 0.2 years; interquartile range, 0.1-0.5) who participated in the Effect of Tight Control Management on CD (CALM) study, at 31 sites, representing 50% of the original CALM patient population. Fifty percent of patients (n = 61) were randomly assigned to a tight control strategy (increased therapy based on fecal level of calprotectin, serum level of C-reactive protein, and symptoms), and 50% were assigned to conventional management. We categorized patients as those who were vs were not in deep remission (CD endoscopic index of severity scores below 4, with no deep ulcerations or steroid treatment, for 8 or more weeks) at the end of the follow-up period (median, 3.02 years; range, 0.05-6.26 years). The primary outcome was a composite of major adverse outcomes that indicate CD progression during the follow-up period: new internal fistulas or abscesses, strictures, perianal fistulas or abscesses, or hospitalization or surgery for CD. Kaplan-Meier and penalized Cox regression with bootstrapping were used to compare composite rates between patients who achieved or did not achieve remission at the end of the follow-up period. RESULTS: Major adverse outcomes were reported for 34 patients (27.9%) during the follow-up period. Significantly fewer patients in deep remission at the end of the CALM study had major adverse outcomes during the follow-up period (P = .01). When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07-0.31) was significantly associated with a lower risk of major adverse outcome. CONCLUSIONS: In an analysis of follow-up data from the CALM study, we associated induction of deep remission in early, moderate to severe CD with decreased risk of disease progression over a median time of 3 years, regardless of tight control or conventional management strategy.

Role of fecal calprotection in predicting endoscopic recurrence in postoperative Crohn's disease.

BACKGROUND AND AIMS: Fecal calprotectin (fCP) has been shown to correlate with endoscopic disease activity in Crohn's disease (CD). The aim of this study was to evaluate its role in predicting early endoscopic recurrence in postoperative CD. METHODS: Patients who underwent CD-related intestinal resection with ileocolonic anastomosis were prospectively followed up until ileocolonoscopy was performed around 12 months post-surgery. Endoscopic recurrence (ER) was defined as modified Rutgeerts score i2b or higher. Endoscopic still images were reviewed by 2 independent reviewers blinded to fCP results. Stool specimens were collected 6 months post-surgery and a multivariate logistic regression model was established to explore the predictive value of fCP for ER. RESULTS: 79 patients were included. FCP was significantly associated with endoscopic recurrence (p = .036). A cut-off value of fCP of 267 µg/g at 6 months post-surgery predicted ER with a sensitivity of 61.8% and a specificity of 72.7% (AUC 0.669). A prediction model subsuming age at diagnosis and fCP 6 months post-surgery were significantly associated with ER (fCP at 6 months [p = .007] and age at diagnosis [p = .004], multivariate analysis). CONCLUSIONS: FCP 6 months after surgery and age at diagnosis predict early ER at 1 year postoperatively. However, the low sensitivity of fCP still suggests the necessity of endoscopy as a gold standard for the assessment of postoperative recurrence of CD.KEY SUMMARYWhat is already known? Fecal calprotectin (fCP) correlates with endoscopic disease activity. Endoscopic recurrence occurs in up to 70% of patients after intestinal resection within 1 year.What are the significant and/or new findings of this study? Fecal calprotectin 6 months post-surgery and age at diagnosis significantly predict endoscopic recurrence at 1 year. Due to low sensitivity fCP cannot replace the necessity of endoscopy for accurate assessment of postoperative recurrence.

Tight control for Crohn's disease with adalimumab-based treatment is cost-effective: an economic assessment of the CALM trial.

OBJECTIVE: To evaluate the cost-effectiveness of an inflammatory biomarker and clinical symptom directed tight control strategy (TC) compared with symptom-based clinical management (CM) in patients with Crohn's disease (CD) naïve to immunosuppressants and biologics using a UK public payer perspective. DESIGN: A regression model estimated weekly CD Activity Index (CDAI)-based transition matrices (remission: CDAI <150, moderate: CDAI ≥150 to <300, severe: CDAI ≥300 to <450, very severe: CDAI ≥450) based on the Effect of Tight Control Management on Crohn's Disease (CALM) trial. A regression predicted hospitalisations. Health utilities and costs were applied to health states. Work productivity was monetised and included in sensitivity analyses. Remission rate, CD-related hospitalisations, adalimumab injections, other direct medical costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. RESULTS: Over 48 weeks, TC was associated with a higher clinical remission (CDAI <150) rate (58.2% vs 46.8%), fewer CD-related hospitalisations (0.124 vs 0.297 events per patient) and more injections of adalimumab (40 mg sc) (mean 31.0 vs 24.7) than CM. TC was associated with 0.032 higher QALYs and £593 higher total medical costs. The ICER was £18 656 per QALY. The ICER was cost-effective in 57.9% of simulations. TC became dominant, meaning less costly but more effective, when work productivity was included. CONCLUSION: A TC strategy as used in the CALM trial is cost-effective compared with CM. Incorporating costs related to work productivity increases the economic value of TC. Cross-national inferences from this analysis should be made with caution given differences in healthcare systems. TRIAL REGISTRATION NUMBER: NCT01235689; Results.

Thumb sucking or nail biting in childhood and adolescence is associated with an increased risk of Crohn's disease: results from a large case-control study.

BACKGROUND: The hygiene hypothesis suggests that a reduction in microbial exposure contributes to an impaired immune response later in life and increases the incidence of immune-mediated diseases such as inflammatory bowel diseases (IBD). Thumb sucking and nail biting are two early habits that modulate the oral microbiota composition and antigen load. OBJECTIVE: We hypothesized a lower risk of Crohn's disease (CD) and ulcerative colitis (UC) in adults with prior thumb sucking and nail biting. METHODS: 918 IBD cases and their 918 siblings without IBD were asked to fill out a survey containing 32 questions on environmental factors in childhood and early adulthood. Prevalence of thumb sucking and/or nail biting at the usually well-remembered time of (1) school enrollment and (2) coming-of-age ceremonies was the predefined combined risk factor of this study. RESULTS: 65% of the patients were female and 57% suffered from CD. About 49% of IBD patients but only 44% of their siblings reported thumb sucking/nail biting at the time of school enrollment or coming-of-age (p = .007). Sensitivity analysis revealed that this difference was observed in patients with CD (50% versus 41%; RR= 1.22; 95% CI 1.09-1.37, p = .001) but not in patients with UC (49% versus 48%; RR= 1.02; 95% CI 0.90-1.17; p = .83). CONCLUSION: Contrary to our expectation and challenging the hygiene hypothesis, we found that common oral habits are not protective against IBD. Instead, nail biting at the time of school enrollment and coming-of-age was a statistically significant risk factor for CD in our cohort. Key summary Evidence available before this study: The hygiene hypothesis suggests that a reduction in microbial exposure due to improved health activities has contributed to an immunological imbalance in the intestine and an increased incidence of allergic and autoimmune diseases. A population-based birth cohort study has demonstrated that thumb-sucking and nail biting in children lead to a reduction of the risk of atopic sensitization, asthma, and hay fever. Added value of this study: Contrary to the hypothesis, thumb sucking and nail biting were not associated with a reduced risk of IBD. Instead, thumb sucking and/or nail biting at the usually well-remembered points in time of school enrollment and of religious or secular coming-of-age ceremonies was associated with a higher risk of Crohn's disease but not of ulcerative colitis. Our data did not support the hygiene hypothesis, one pathogenic concept in the context of IBD.

Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial.

BACKGROUND: Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. METHODS: CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 µg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. FINDINGS: Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran-Mantel-Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9-28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group. INTERPRETATION: CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. FUNDING: AbbVie.

[Ustekinumab - Current position]. / Ustekinumab ­ eine Standortbestimmung.

The present review by the IBD-Dach group provides a comprehensive summary of the mode of action, clinical development, approval, efficacy and safety aspects of the novel anti-p40 antibody Ustekinumab. The review provides current data, including the large clinical trials as well as smaller case series and work outside the field of inflammatory bowel diseases for shedding more light into special situations. Together, the data indicate that Ustekinumab shows clinical efficacy as well as a good safety profile for the treatment of Crohn's disease.

[Second Austrian consensus on the safe use of anti-TNFα-antibodies in patients with inflammatory bowel diseases]. / Zweiter österreichischer Konsensus zur sicheren Anwendung von anti-TNF-α-Antikörpern bei chronisch-entzündlichen Darmerkrankungen.

Anti-TNFα-antibodies have revolutionized the therapy of inflammatory bowel diseases and other immune-mediated inflammatory diseases. Due to the increasing application of these substances, the Working Group of Inflammatory Bowel Diseases of the Austrian Association of Gastroenterology and Hepatology intended to update their consensus report on the safe use of Infliximab (published in 2010) and to enlarge its scope to cover all anti-TNFα-antibodies. The present consensus report summarizes the current evidence on the safe use of anti-TNFα-antibodies and covers the following topics: general risk of infection, bacterial infections (i. e., Clostridium difficile, Tuberculosis, food hygiene), Pneumocystis jiroveci, viral infections (i. e., Hepatitis B, Hepatitis C, HIV, CMV, VZV), vaccination in general and recommendation for vaccines, gastrointestinal aspects (i. e., perianal fistula, abdominal fistula, intestinal strictures, stenosis and bowel obstruction), dermatologic aspects (skin malignancies, eczema-like drug-related skin eruption), infusion reactions and immunogenicity, demyelinating diseases, hepatotoxicity, haematotoxicity, congestive heart failure, risk and history of malignancies, and pregnancy and breast feeding. For practical reasons, the relevant aspects are summarized in a checklist which is divided into two parts: issues to be addressed before therapy and issues to be addressed during therapy.

Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.

Platelets Toll-like receptor-4 in Crohns disease.

BACKGROUND: Platelets are activated in Crohn's disease (CD) and interplay with leukocytes. Engagement of Toll-like receptor-4 (TLR-4), which is expressed in human platelets, may be involved in crosstalks between platelets and leukocytes leading to their mutual activation for host defense. MATERIALS AND METHODS: Human neutrophil peptides (HNPs), lipoprotein binding peptides, and sCD14 were determined by enzyme-linked immunosorbent assays in 42 patients with active CD, in 43 patients with CD in remission, and in 30 healthy individuals. Neutrophil-platelet aggregates and binding of the TLR-4 monoclonal antibody to platelets were determined by flow cytometry. RESULTS: Levels of HNPs were higher in patients with CD than in controls (P = 0.0003 vs. active CD and P = 0.01 vs. CD in remission). Likewise, neutrophils with adhering platelets were higher in patients with active CD than in controls (P = 0.004). Binding of the TLR-4 antibody in patients with active CD was similar to that in controls, while patients in remission had significantly higher binding capacities (P = 0.59 and P = 0.003). Incubation of plasma from patients with active disease or patients in remission with platelets from healthy controls confirmed lower binding of the TLR-4 antibody in the presence of plasma from active diseased patients compared to controls (P = 0.039), possibly due to high levels of lipopolysaccharides, as suggested by high levels of sCD14 and lipoprotein binding protein. CONCLUSION: Our study indicates involvement of platelet TLR-4 in enhancing the secretion of antimicrobial peptides from neutrophils. While platelet aggregation can be due to a variety of mechanisms in inflammatory disease, the mutual activation of platelets and neutrophils may augment host defense.

A 1-year trial of repeated high-dose intravenous iron isomaltoside 1000 to maintain stable hemoglobin levels in inflammatory bowel disease.

OBJECTIVE: Iron isomaltoside 1000 (Monofer®) is a high-dose intravenous (IV) iron, which in a recent 8 weeks trial in inflammatory bowel disease (IBD) subjects with iron deficiency anemia (IDA) demonstrated good tolerability and efficacy. The present trial is an extension to this trial, which evaluates the need for additional high IV iron doses to maintain a stable hemoglobin (Hb) ≥12.0 g/dl. MATERIAL AND METHODS: This was a prospective, open-label, 12 months trial of European IBD subjects willing to participate after completing the lead-in trial. Subjects were allowed re-dosing with 500-2000 mg single doses of iron isomaltoside 1000 infused over ∼15 min at 3 months intervals depending on a predefined algorithm. Outcome measures included Hb, safety parameters and need for additional iron dosing. RESULTS: A total of 39 subjects were enrolled of which 34 subjects required re-dosing with a median cumulative 1-year dose of 1.8 g (mean cumulative dose 2.2 g). The mean (SD) Hb was 12.3 (1.5) g/dl at baseline, 12.8 (1.6) g/dl at 3 months, 12.8 (1.6) g/dl at 6 months, 12.9 (1.4) g/dl at 9 months and 12.9 (1.6) g/dl at 12 months. Seventy-four percent of subjects who had an Hb ≥12.0 g/dl at baseline were able to maintain Hb ≥12.0 g/dl till the end of the trial at 12 months. Nonserious probably related hypersensitivity reactions without significant hypotension were reported at the beginning of the infusion in two subjects, who recovered without sequelae. CONCLUSION: Repeated treatment of iron deficiency with iron isomaltoside 1000 could avoid episodes of IDA without major safety issues.

Withdrawal of long-term maintenance treatment with azathioprine tends to increase relapse risk in patients with Crohn's disease.

BACKGROUND AND AIM: Many patients with quiescent Crohn's disease are maintained on long-term treatment with azathioprine (AZA), but controlled data are limited. We aimed to evaluate the efficacy of AZA therapy for more than 4 years to maintain clinical remission. METHODS: We performed a randomized double-blind placebo-controlled AZA withdrawal trial with a follow-up period of 24 months. Patients had to have continuous AZA therapy ≥ 4 years without exacerbation of disease during the 12 months before enrollment, and a Crohn's disease activity index < 150 at baseline. Patients were randomized to continue on AZA or switch to placebo. The primary endpoint was time to clinical relapse during follow-up. RESULTS: After inclusion of 52 patients, the trial was stopped prematurely due to slow recruitment. During the 2-year follow-up, clinical relapse occurred in 4 of 26 (15 %) patients on continued AZA and in 8 of 26 (31 %) patients on placebo. Time to clinical relapse averaged 22.3 months (95 % CI 20.6-24.0) on AZA and 19.2 months (95 % CI 16.4-22.1) on placebo (p = 0.20). According to life-table analysis, the proportion of patients in remission after 12 and 24 months was 96 ± 4 and 86 ± 7 % in patients receiving AZA versus 76 ± 8 and 68 ± 9 % in patients receiving placebo (month 12, p = 0.035; month 24, p = 0.30). A higher AZA dose at enrollment was an independent predictor for relapse (p < 0.05). CONCLUSIONS: AZA withdrawal resulted in a significantly increased relapse risk after 1 year and a nonstatistically significant trend for relapse after 2 years. Our results are in line with previous observations.

Prediction of Response to Systemic Corticosteroids in Active UC by Microbial Composition-A Prospective Multicenter Study.

BACKGROUND: Corticosteroids are used for induction of remission in patients with moderately to severely active ulcerative colitis. However, up to one-third of patients fail to this therapy. We investigated if fecal microbial composition or its metabolic capacity are associated with response to systemic corticosteroids. METHODS: In this prospective, multicenter study, patients with active ulcerative colitis (Lichtiger score ≥4) receiving systemic corticosteroids were eligible. Data were assessed and fecal samples collected before and after 4 weeks of treatment. Patients were divided into responders (decrease of Lichtiger Score ≥50%) and nonresponders. The fecal microbiome was assessed by the 16S rRNA gene marker and analyzed with QIIME 2. Microbial metabolic pathways were predicted using parsimonious flux balance analysis. RESULTS: Among 93 included patients, 69 (74%) patients responded to corticosteroids after 4 weeks. At baseline, responders could not be distinguished from nonresponders by microbial diversity and composition, except for a subgroup of biologic-naïve patients. Within 4 weeks of treatment, responders experienced changes in beta diversity with enrichment of ascribed beneficial taxa, including Blautia, Anaerostipes, and Bifidobacterium, as well as an increase in predicted butyrate synthesis. Nonresponders had only minor longitudinal taxonomic changes with a significant increase of Streptococcus salivarius and a microbial composition shifting away from responders. CONCLUSION: Baseline microbial diversity and composition seem to be of limited use to predict response to systemic corticosteroids in active ulcerative colitis. Response is longitudinally associated with restoration of microbial composition and its metabolic capacity.

Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Tofacitinib in the treatment of ulcerative colitis : A position paper issued by the Inflammatory Bowel Disease Working Group of the Austrian Society of Gastroenterology and Hepatology (ÖGGH).

Ulcerative colitis (UC) is one of the main forms of inflammatory bowel disease (IBD). Despite the widening range of drug treatment options, primary nonresponse, secondary loss of response as well as adverse events call for additional treatment alternatives.Tofacitinib is an oral small-molecule drug of the class of Janus kinase inhibitors which, in the European Union, was approved for the treatment of moderate to severe active UC in August 2018. This position paper, drawn up by the IBD Working Group of the Austrian Society of Gastroenterology and Hepatology, summarizes the mechanism of action, clinical development, marketing authorization status, efficacy and safety of tofacitinib. Also, by providing a synopsis of available data from both pivotal and post-marketing studies, clinical aspects of specific interest are highlighted and discussed.The available body of evidence indicates that tofacitinib is an additional effective medication for the treatment of UC that exhibits a good safety profile. This position paper aims at optimizing the safe and effective use of tofacitinib in daily clinical practice.

Management of suspected and known eosinophilic esophagitis-a nationwide survey in Austria.

INTRODUCTION: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus with increasing incidence and dysphagia as the main symptom. The management of suspected or known EoE by Austrian endoscopists has not been investigated yet. METHODS: A web-based survey with 13 questions about the management of EoE was sent to endoscopists via the Austrian Society of Gastroenterology and Hepatology (ÖGGH). RESULTS: A total of 222 endoscopists (74% gastroenterologists, 23% surgeons, and 2% pediatricians; 68% working in a hospital) from all 9 states participated. In patients with dysphagia but a normal appearing esophagus, 85% of respondents reported always taking biopsies; however, surgeons were less likely to obtain biopsies compared to gastroenterologists ("always" 69% vs. 90%, "sometimes" 29% vs. 10%, "never" 2% vs. 0%, p < 0.001). The approved budesonide orodispersible tablet is the preferred first-line drug used in EoE, ahead of proton pump inhibitors (PPI). Only 65% of participants monitor the patients by endoscopy and histology after 12 weeks of induction therapy, 26% do not continue maintenance therapy, and 22% monitor patients only when symptomatic. CONCLUSION: The vast majority of Austrian endoscopists adhere to the European and US guidelines in cases of suspected EoE. In contrast, despite the chronic disease course, a significant percentage of providers indicate not to use maintenance therapy and monitor the patients routinely.

The accelerated waning of immunity and reduced effect of booster in patients treated with bDMARD and tsDMARD after SARS-CoV-2 mRNA vaccination.

Objectives: This study aimed to assess the duration of humoral responses after two doses of SARS-CoV-2 mRNA vaccines in patients with inflammatory joint diseases and IBD and booster vaccination compared with healthy controls. It also aimed to analyze factors influencing the quantity and quality of the immune response. Methods: We enrolled 41 patients with rheumatoid arthritis (RA), 35 with seronegative spondyloarthritis (SpA), and 41 suffering from inflammatory bowel disease (IBD), excluding those receiving B-cell-depleting therapies. We assessed total anti-SARS-CoV-2 spike antibodies (Abs) and neutralizing Ab titers 6 months after two and then after three doses of mRNA vaccines compared with healthy controls. We analyzed the influence of therapies on the humoral response. Results: Patients receiving biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) showed reduced anti-SARS-CoV-2 S Abs and neutralizing Ab titers compared with HC or patients receiving conventional synthetic (cs)DMARDs 6 months after the first two vaccination doses. Anti-SARS-CoV-2 S titers of patients with b/tsDMARDs declined more rapidly, leading to a significant reduction in the duration of vaccination-induced immunity after two doses of SARS-CoV-2 mRNA vaccines. While 23% of HC and 19% of patients receiving csDMARDs were without detectable neutralizing Abs 6 months after the first two vaccination doses, this number was 62% in patients receiving b/tsDMARDs and 52% in patients receiving a combination of csDMARDs and b/tsDMARDs. Booster vaccination led to increased anti-SARS-CoV-2 S Abs in all HC and patients. However, anti-SARS-CoV-2 S Abs after booster vaccination was diminished in patients receiving b/tsDMARDs, either alone or in combination with csDMARDs compared to HC. Conclusion: Patients receiving b/tsDMARDs have significantly reduced Abs and neutralizing Ab titers 6 months after mRNA vaccination against SARS-CoV-2. This was due to a faster decline in Ab levels, indicating a significantly reduced duration of vaccination-induced immunity compared with HC or patients receiving csDMARDs. In addition, they display a reduced response to a booster vaccination, warranting earlier booster vaccination strategies in patients under b/tsDMARD therapy, according to their specific Ab levels.

Lower magnitude and faster waning of antibody responses to SARS-CoV-2 vaccination in anti-TNF-α-treated IBD patients are linked to lack of activation and expansion of cTfh1 cells and impaired B memory cell formation.

BACKGROUND: Patients with inflammatory bowel disease (IBD) and healthy controls received primary SARS-CoV-2-mRNA vaccination and a booster after six months. Anti-TNF-α-treated patients showed significantly lower antibody (Ab) levels and faster waning than α4ß7-integrin-antagonist recipients and controls. This prospective cohort study aimed to elucidate the underlying mechanisms on the basis of circulating T-follicular helper cells (cTfh) and B memory cells. METHODS: We measured SARS-CoV-2- Wuhan and Omicron specific Abs, B- and T-cell subsets at baseline and kinetics of Spike (S)-specific B memory cells along with distributions of activated cTfh subsets before and after primary and booster vaccination. FINDINGS: Lower and faster waning of Ab levels in anti-TNF-α treated IBD patients was associated with low numbers of total and naïve B cells vs. expanded plasmablasts prior to vaccination. Along with their low Ab levels against Wuhan and Omicron VOCs, reduced S-specific B memory cells were identified after the 2nd dose which declined to non-detectable after 6 months. In contrast, IBD patients with α4ß7-integrin-antagonists and controls mounted and retained high Ab levels after the 2nd dose, which was associated with a pronounced increase in S-specific B memory cells that were maintained or expanded up to 6 months. Booster vaccination led to a strong increase of Abs with neutralizing capacity and S-specific B memory cells in these groups, which was not the case in anti-TNF-α treated IBD patients. Of note, Ab levels and S-specific B memory cells in particular post-booster correlated with the activation of cTfh1 cells after primary vaccination. INTERPRETATIONS: The reduced magnitude, persistence and neutralization capacity of SARS-CoV-2 specific Abs after vaccination in anti-TNF-α-treated IBD patients were associated with impaired formation and maintenance of S-specific B memory cells, likely due to absent cTfh1 activation leading to extra-follicular immune responses and diminished B memory cell diversification. These observations have implications for patient-tailored vaccination schedules/vaccines in anti-TNF-α-treated patients, irrespective of their underlying disease. FUNDING: The study was funded by third party funding of the Institute of Specific Prophylaxis and Tropical Medicine at the Medical University Vienna. The funders had no role in study design, data collection, data analyses, interpretation, or writing of report.