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Ustekinumab, is a new therapy for patients with IBD, especially for patients suffering from Crohn's disease (CD) who did not respond to anti-TNF treatment. To shed light on the longitudinal effect of ustekinumab on the immune system, we investigated the effect on skin and gut microbiota composition, specific immune response to commensals, and various serum biomarkers. We recruited 11 patients with IBD who were monitored over 40 weeks of ustekinumab therapy and 39 healthy controls (HC). We found differences in the concentrations of serum levels of osteoprotegerin, TGF-β1, IL-33, and serum IgM antibodies against Lactobacillus plantarum between patients with IBD and HC. The levels of these biomarkers did not change in response to ustekinumab treatment or with disease improvement during the 40 weeks of observation. Additionally, we identified differences in stool abundance of uncultured Subdoligranulum, Faecalibacterium, and Bacteroides between patients with IBD and HC. In this preliminary study, we provide a unique overview of the longitudinal monitoring of fecal and skin microbial profiles as well as various serum biomarkers and humoral and cellular response to gut commensals in a small cohort of patients with IBD on ustekinumab therapy.

Background. Tumor necrosis factor-alpha (TNF-α) agonists revolutionized therapeutic algorithms in inflammatory bowel disease (IBD) management. However, approximately every third IBD patient does not respond to this therapy in the long term, which delays efficient control of the intestinal inflammation. Methods. We analyzed the power of serum biomarkers to predict the failure of anti-TNF-α. We collected serum of 38 IBD patients at therapy prescription and 38 weeks later and analyzed them with relation to therapy response (no-, partial-, and full response). We used enzyme-linked immunosorbent assay to quantify 16 biomarkers related to gut barrier (intestinal fatty acid-binding protein, liver fatty acid-binding protein, trefoil factor 3, and interleukin (IL)-33), microbial translocation, immune system regulation (TNF-α, CD14, lipopolysaccharide-binding protein, mannan-binding lectin, IL-18, transforming growth factor-β1 (TGF-β1), osteoprotegerin (OPG), insulin-like growth factor 2 (IGF-2), endocrine-gland-derived vascular endothelial growth factor), and matrix metalloproteinase system (MMP-9, MMP-14, and tissue inhibitors of metalloproteinase-1). Results. We found that future full-responders have different biomarker profiles than non-responders, while partial-responders cannot be distinguished from either group. When future non-responders were compared to responders, their baseline contained significantly more TGF-β1, less CD14, and increased level of MMP-9, and concentration of these factors could predict non-responders with high accuracy (AUC = 0.938). Interestingly, during the 38 weeks, levels of MMP-9 decreased in all patients, irrespective of the outcome, while OPG, IGF-2, and TGF-β1 were higher in non-responders compared to full-responders both at the beginning and the end of the treatment. Conclusions. The TGF-β1 and CD14 can distinguish non-responders from responders. The changes in biomarker dynamics during the therapy suggest that growth factors (such as OPG, IGF-2, and TGF-β) are not markedly influenced by the treatment and that anti-TNF-α therapy decreases MMP-9 without influencing the treatment outcome.

Crohn’s disease (CD) and ulcerative colitis (UC) are two forms of inflammatory bowel disease (IBD), where the role of gut but not skin dysbiosis is well recognized. Inhibitors of TNF have been successful in IBD treatment, but up to a quarter of patients suffer from unpredictable skin adverse events (SkAE). For this purpose, we analyzed temporal dynamics of skin microbiota and serum markers of inflammation and epithelial barrier integrity during anti-TNF therapy and SkAE manifestation in IBD patients. We observed that the skin microbiota signature of IBD patients differs markedly from healthy subjects. In particular, the skin microbiota of CD patients differs significantly from that of UC patients and healthy subjects, mainly in the retroauricular crease. In addition, we showed that anti-TNF-related SkAE are associated with specific shifts in skin microbiota profile and with a decrease in serum levels of L-FABP and I-FABP in IBD patients. For the first time, we showed that shifts in microbial composition in IBD patients are not limited to the gut and that skin microbiota and serum markers of the epithelium barrier may be suitable markers of SkAE during anti-TNF therapy.

Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract that have been linked to microbiome dysbiosis and immune system dysregulation. We investigated the longitudinal effect of anti-TNF therapy on gut microbiota composition and specific immune response to commensals in IBD patients. The study included 52 patients tracked over 38 weeks of therapy and 37 healthy controls (HC). To characterize the diversity and composition of the gut microbiota, we used amplicon sequencing of the V3V4 region of 16S rRNA for the bacterial community and of the ITS1 region for the fungal community. We measured total antibody levels as well as specific antibodies against assorted gut commensals by ELISA. We found diversity differences between HC, Crohn’s disease, and ulcerative colitis patients. The bacterial community of patients with IBD was more similar to HC at the study endpoint, suggesting a beneficial shift in the microbiome in response to treatment. We identified factors such as disease severity, localization, and surgical intervention that significantly contribute to the observed changes in the gut bacteriome. Furthermore, we revealed increased IgM levels against specific gut commensals after anti-TNF treatment. In summary, this study, with its longitudinal design, brings insights into the course of anti-TNF therapy in patients with IBD and correlates the bacterial diversity with disease severity in patients with ulcerative colitis (UC).

Abstract INTRODUCTION Both primary strictures and secondary anastomotic strictures are common complications in patients with inflammatory bowel diseases (IBD), especially Crohn’s disease (CD). Balloon dilation has been the gold standard in the endoscopic treatment of these strictures. Endoscopic stricturotomy (ESt, Figure 1) represents a promising novel approach, however, the data published on this method so far has been limited to a small sample and few sites. METHODS All ESts performed in IBD patients between September 2018 and April 2021 in our tertiary IBD center were included. Data on demographics, disease characteristics, procedure details and outcomes were analyzed. Technical success was defined as an ability to pass the scope through the stricture following the procedure. Complications included perforation and immediate or delayed bleeding with the need of intervention or hospitalization. RESULTS In total, 92 procedures were performed in 67 patients (60 with Crohn’s disease, CD, and 7 with ulcerative colitis, UC) Among these 46.3% were males. Mean age was 43.9±12.5 years and mean disease duration was 14.6±9.7 years. Single ESt was done in 73.1% (49) of patients, while 26.9% (18) required multiple procedures. Most common location of stricture was surgical anastomosis site (82, 89.1%), while remaining 10 were located at anal canal (de novo stricture). Anastomotic strictures included ileo-colonic (64.1%), colo-colonic (9.8%), ileo-rectal (3.3%), and ileal pouch-anal (12.0%) anastomoses. Previous endoscopic balloon dilation (EBD) was attempted in 53.3% of the procedures, 27.2% of the analyzed procedures were preceded by earlier ESt. Technical success was achieved in 83 ESts (90.2%), complications occurred in four cases (all delayed bleeding, managed conservatively). After the mean follow-up time of 18.1±10.0 months, cumulative probability of reintervention (ESt, EBD or surgery) at 6 months was 30.2% (95% CI 15.6-46.2%), 40.3% (95% CI 25.5-54.6%) at 12 months and 48.8% (95% CI 34,0-62,1%) at 18 months (Figure 2). Time to reintervention was not significantly affected by previous intervention, age of the anastomosis, sex or age of the patients, concurrent therapy and specific ESt technique employed. CONCLUSION ESt is a novel endoscopic technique, which is both efficacious and safe to be performed in patients with IBD-related strictures. Figure 1. Ileo-colonic anastomosis after the endoscopic stricturotomy (left) and clipping (right) Figure 2. Cumulative probability of reintervention (endoscopic stricturotomy, balloon dilation or surgery) after endoscopic stricturotomy

Abstract Background Patients with inflammatory bowel disease (IBD) on immune-modifying treatment could be at an increased risk for severe coronavirus disease 2019 (COVID-19); thus, data on the efficacy and safety of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines are essential. We conducted a prospective study of IBD patients vaccinated with BNT162b2, CX-024414, and ChAdOx1 nCoV-19 vaccines. The aim was to evaluate the rate and magnitude of seroconversion, assess the effect of different immune-modifying treatment modalities on the magnitude of anti-SARS-CoV-2 IgG antibody levels, and analyze the impact of anti-SARS-CoV-2 vaccination on the inflammatory biomarkers of IBD. Methods The study included 602 IBD patients and 168 immunocompetent health care workers serving as controls. Serum anti-SARS-CoV-2 IgG antibodies were measured by chemiluminescent microparticle immunoassay before the vaccination and 8 weeks after the vaccination. Results Of IBD patients, 82.2% were receiving biological treatment: most of them were treated with antitumor necrosis factor (TNF)-α inhibitors (48.5%), and just under half of them were treated with concomitant thiopurines or methotrexate, followed by vedolizumab (18.6%) and ustekinumab (15.1%). Only 8.1% of patients were on 5-aminosalicylates, and a minority (2.2%) were treatment-free. The postvaccine seropositivity rate among IBD patients and controls was 97.8% vs 100%. Median anti-SARS-CoV-2 IgG levels were lower among IBD recipients of ChAdOx1 nCoV-19 compared with 2 other vaccines (P < .0001) and control ChAdOx1 nCoV-19 recipients (P = .01). No correlation was found between serum trough levels and anti-SARS-CoV-2 IgG concentrations for any of the biological drugs used. The TNF-α inhibitors with concomitant immunosuppressive treatment but no other treatment modalities were associated with a lower postvaccination antibody response (P < .0001). When evaluating the laboratory activity of IBD by C-reactive protein and fecal calprotectin levels, no significant differences were found before the vaccination and 8 weeks after its completion. Conclusions Our findings warrant particular attention to the anti-SARS-CoV-2 vaccination of IBD patients treated with TNF-α inhibitors with concomitant immunomodulators and show the priority of mRNA vaccines in this specific group of patients. This prospective single-center study on 602 inflammatory bowel disease (IBD) patients and 168 healthy controls shows that vaccination against COVID-19 is effective and safe in patients with IBD. It warrants particular attention to the anti-SARS-CoV-2 vaccination of IBD patients treated with TNF-α inhibitors with immunomodulators, shows priority of mRNA vaccines in this specific group of patients, and confirms that IBD patients can continue their high-efficacy immune-modifying therapy, including biological treatment, even during the anti-SARS-CoV-2 vaccination.

Abstract INTRODUCTION Despite significant impact biological treatment had on prospects of patients with IBD, there is still a substantial proportion of patients with either secondary loss of response or primary non-response to therapy. Strategies to avert treatment failure include dose optimization, selection of drugs with different mechanism of action or recently combination of two different targeted molecules in cases where inflammatory activity is not under control. METHODS Patients failing on all available treatment modalities in whom surgery was not possible or was to be avoided and in whom combined treatment with two biological agents or biological agent and a small molecule was started were included. Data on demographics, treatment details, treatment persistence and disease activity including laboratory parameters and clinical activity indices - Harvey-Bradshaw for Crohn’s disease (CD) and partial Mayo score for ulcerative colitis (UC) were collected. Treatment response was evaluated using simple physician’s global assessment (PGA) as no, partial or full response. RESULTS In total, 25 patients were started on dual therapy between September 2020 and May 2021, 68% with CD and 32% with UC. Mean age of the cohort was 34.4±10.9 years, 56% were males and 44% females. Mean disease duration at baseline was 11.2±6.6 years. The follow-up continued until September 2021, median survival on therapy was 45.4 weeks and it was stopped in 40% of patients during the follow-up period. Reasons for termination included poor response, allergic reaction, unsatisfactory pharmacokinetics, advancement to surgery and denial by health insurance company. The included patients were complicated with low age of onset in CD (20.7±8.6 years), dominantly ileocolonic involvement (77%), 35% with proximal disease and 35% with perianal disease. Over 88% underwent abdominal surgery in the past. Two thirds of patients had extensive UC. Various combinations of drugs have been used with prevailing combination of ustekinumab (UST) and vedolizumab (VDZ) (41%) and UST with adalimumab (35%) in CD and VDZ with tofacitinib (63%) in UC. While in CD the overall clinical PGA response was poor with only 30% of patients at least partially responding at week 30, in UC 80% of patients were responders at week 30 (Figures 1 and 2). Apart from two infusion reactions, no other adverse events raising safety concerns occurred during the follow-up. Direct costs of the dual therapy were estimated to be 5-8 times higher as compared to the standard therapy with anti-TNF drug. Figure 1. Fecal calprotectin and partial Mayo score in ulcerative colitis patients on dual therapy Figure 2. Clinical response to dual therapy as evaluated by physician’s global assessment CONCLUSIONS Dual therapy proved to be feasible option that can be employed without significant safety concerns in a carefully selected group of patients. Patients with colonic involvement seemed to benefit the most from the treatment, however, high incurred costs currently limit more widespread use of dual therapy in common clinical practice.

Tumor necrosis factor-alpha (TNF- ) agonists revolutionized therapeutic algorithms in inflammatory bowel disease (IBD) management. However, approximately every third IBD patient does not respond to this therapy in the long term, which delays efficient control of the intestinal inflammation. We analyzed the power of serum biomarkers to predict the failure of anti-TNF- . We collected serum of 38 IBD patients at therapy prescription and 38 weeks later and analyzed them with relation to therapy response (no-, partial-, and full response). We used enzyme-linked immunosorbent assay to quantify 16 biomarkers related to gut barrier (intestinal fatty acid-binding protein, liver fatty acid-binding protein, trefoil factor 3, and interleukin (IL)-33), microbial translocation, immune system regulation (TNF- , CD14, lipopolysaccharide-binding protein, mannan-binding lectin, IL-18, transforming growth factor- 1 (TGF- 1), osteoprotegerin (OPG), insulin-like growth factor 2 (IGF-2), endocrine-gland-derived vascular endothelial growth factor), and matrix metalloproteinase system (MMP-9, MMP-14, and tissue inhibitors of metalloproteinase-1). We found that future full-responders have different biomarker profiles than non-responders, while partial-responders cannot be distinguished from either group. When future non-responders were compared to responders, their baseline contained significantly more TGF- 1, less CD14, and increased level of MMP-9, and concentration of these factors could predict non-responders with high accuracy (AUC = 0.938). Interestingly, during the 38 weeks, levels of MMP-9 decreased in all patients, irrespective of the outcome, while OPG, IGF-2, and TGF- 1 were higher in non-responders compared to full-responders both at the beginning and the end of the treatment. The TGF- 1 and CD14 can distinguish non-responders from responders. The changes in biomarker dynamics during the therapy suggest that growth factors (such as OPG, IGF-2, and TGF- ) are not markedly influenced by the treatment and that anti-TNF- therapy decreases MMP-9 without influencing the treatment outcome.

Interdisciplinární průvodce jedinečným terénem mezi Adamovem na západě a Křtinami na východě upozorňuje \"poutníka\" na zajímavosti z různých přírodních i společenskovědních oborů. Josefovské a Křtinské údolí jsou neopakovatelným krajinným jevem, jehož studium umožňuje pochopit dlouhý vývoj celého Moravského krasu. Zasvěcený a originální text kolektivu odborníků pracuje s nejnovějšími informacemi, které doplňuje množství fotografií, map a tabulek.