Therapie der CED bei Steroidversagen : Immunsuppressiva oder Biologika? [Therapy of steroid resistant inflammatory bowel disease Immunomodulators or biologicals?]

Although systemic corticosteroids are often successfully applied for induction of clinical response and remission of inflammatory bowel disease (IBD) patients presenting with a flare, a proportion of these treated patients present with a primary non-response to steroids, resistance or steroid dependence. Long-term therapy with corticosteroids for treatment of IBD should be avoided given the high frequency of adverse treatment effects. This article highlights the indications for the use of immunomodulators (e.g. azathioprine, 6-mercaptopurine and methotrexate), drugs directed against tumor necrosis factor (anti-TNF) as well as calcineurin inhibitors (e.g. cyclosporine and tacrolimus)

Eosinophilic Esophagitis beyond Eosinophils - an Emerging Phenomenon Overlapping with Eosinophilic Esophagitis: Collegium Internationale Allergologicum (CIA) Update 2023.

Having long been considered the mainstay in eosinophilic esophagitis (EoE) diagnosis and pathogenesis, the role of eosinophils has been questioned and might be less important than previously thought. It is well known now that EoE is a Th2-mediated disease with many more disease features than eosinophilic infiltration. With more knowledge on EoE, less pronounced phenotypes or nuances of the disease have become apparent. In fact, EoE might be only the tip of the iceberg (and the most extreme phenotype) with several variant forms, at least three, lying on a disease spectrum. Although a common (food induced) pathogenesis has yet to be confirmed, gastroenterologists and allergologists should be aware of these new phenomena in order to further characterize these patients. In the following review, we discuss the pathogenesis of EoE, particularly those mechanisms beyond eosinophilic infiltration of the esophageal mucosa, non-eosinophilic inflammatory cell populations, the new disease entity EoE-like disease, variant forms of EoE, and the recently coined term mast cell esophagitis

Current concepts in eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a disease entity first described in the 1990s, but showing an increasing incidence that is characterized clinically by esophageal dysfunction and histologically by a striking eosinophil infiltration. This article discusses new aspects of the pathogenesis, symptoms, diagnosis, and treatment of EoE. EoE affects both children and adults and is frequently associated with atopic disease and IgE sensitization. Barrier dysfunction and T‑helper 2 inflammation are considered to be pathogenetically important factors. Recently, a proton pump inhibitor (PPI)-sensitive EoE subtype as well as an EoE-like disorder have been described. Research in recent years has contributed to a better understanding of the disease spectrum and pathogenesis of EoE, including genetic dispositions, thereby laying the foundation for innovative treatment approaches

Comparison of different biopsy forceps models for tissue sampling in eosinophilic esophagitis.

Background and aims: Eosinophilic esophagitis (EoE) is a mixed inflammatory and fibrostenotic disease. Unlike superficial inflammatory changes, subepithelial fibrosis is not routinely sampled in esophageal biopsies. This study aimed to evaluate the efficacy and safety of deep esophageal sampling with four different types of biopsy forceps. Patients and methods: In this cross-sectional study, esophageal biopsies were taken in 30 adult patients by one expert endoscopist. Biopsies sampled from distal esophagus using a static jaw forceps (Olympus, FB-11K-1) were compared with proximal biopsies sampled with static jaw (Olympus, FB-45Q-1), alligator jaw (Olympus, FB-210K), and large-capacity forceps (Boston Scientific, Radial Jaw 4). One pathologist calculated the surface area of epithelial and subepithelial layers in hematoxylin and eosin (H&E)-stained biopsies. Results: Subepithelial tissue was acquired in 97 % (static jaw FB-11K-1), 93 % (static jaw FB-45Q-1), 80 % (alligator jaw), and 55 % (large-capacity) of samples. Median (interquartile [IQR]) ratios of surface area of epithelial to subepithelial tissue were: static jaw FB-45Q-1, 1.07 (0.65 - 4.465); static jaw FB-11K-1, 1.184 (0.608 - 2.545); alligator jaw, 2.353 (1.312 - 4.465); and large-capacity, 2.71 (1.611 - 4.858). The static jaw models obtained a larger surface area of subepithelial tissue compared with the alligator jaw (P < 0.001 and P = 0.037, for FB-11K-1 and FB-45Q-1, respectively) and the large-capacity forceps (P < 0.001, for both static jaw models). No esophageal perforations occurred. Conclusions: The static jaw forceps models allowed sampling of subepithelial tissue in > 90 % of biopsies and appear to be superior to alligator or large-capacity forceps in sampling larger amounts of subepithelial tissue

Prevalence and risk factors for therapy escalation in ulcerative colitis in the Swiss IBD Cohort Study

BACKGROUND: Physicians traditionally treat ulcerative colitis (UC) using a step-up approach. Given the paucity of data, we aimed to assess the cumulative probability of UC-related need for step-up therapy and to identify escalation-associated risk factors. METHODS: Patients with UC enrolled into the Swiss IBD Cohort Study were analyzed. The following steps from the bottom to the top of the therapeutic pyramid were examined: (1) 5-aminosalicylic acid and/or rectal corticosteroids, (2) systemic corticosteroids, (3) immunomodulators (IM) (azathioprine, 6-mercaptopurine, methotrexate), (4) TNF antagonists, (5) calcineurin inhibitors, and (6) colectomy. RESULTS: Data on 996 patients with UC with a median disease duration of 9 years were examined. The point estimates of cumulative use of different treatments at years 1, 5, 10, and 20 after UC diagnosis were 91%, 96%, 96%, and 97%, respectively, for 5-ASA and/or rectal corticosteroids, 63%, 69%, 72%, and 79%, respectively, for systemic corticosteroids, 43%, 57%, 59%, and 64%, respectively, for IM, 15%, 28%, and 35% (up to year 10 only), respectively, for TNF antagonists, 5%, 9%, 11%, and 12%, respectively, for calcineurin inhibitors, 1%, 5%, 9%, and 18%, respectively, for colectomy. The presence of extraintestinal manifestations and extended disease location (at least left-sided colitis) were identified as risk factors for step-up in therapy with systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and surgery. Cigarette smoking at diagnosis was protective against surgery. CONCLUSIONS: The presence of extraintestinal manifestations, left-sided colitis, and extensive colitis/pancolitis at the time of diagnosis were associated with use of systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and colectomy during the disease course

Expression Patterns of TNFα, MAdCAM1, and STAT3 in Intestinal and Skin Manifestations of Inflammatory Bowel Disease.

Pathogenesis of cutaneous extraintestinal manifestations [EIM] in inflammatory bowel disease [IBD] remains elusive. Efficacy of anti-TNF agents suggests TNF-dependent mechanisms. The role of other biologics, such as anti-integrins or JAK-inhibitors, is not yet clear. We performed immunohistochemistry for TNFα, NFκB, STAT1/STAT3, MAdCAM1, CD20/68, caspase 3/9, IFNγ, and Hsp-27/70 on 240 intestinal [55 controls, 185 IBD] and 64 skin biopsies [11 controls, 18 erythema nodosum [EN], 13 pyoderma gangenosum [PG], 22 psoriasis]. A semiquantitative score [0-100%] was used for evaluation. TNFα was upregulated in intestinal biopsies from active Crohn`s disease [CD] vs controls [36.2 vs 12.1, p < 0.001], but not ulcerative colitis [UC: 17.9]. NFκB, however, was upregulated in intestinal biopsies from both active CD and UC [43.2 and 34.5 vs 21.8, p < 0.001 and p = 0.017, respectively]. TNFα and NFκB were overexpressed in skin biopsies from EN, PG, and psoriasis. No MAdCAM1 overexpression was seen in skin tissues, whereas it was upregulated in active UC vs controls [57.5 vs 35.4, p = 0.003]. STAT3 was overexpressed in the intestinal mucosa of active and non-active IBD, and a similar upregulation was seen in skin biopsies from EN [84.7 vs 22.3, p < 0.001] and PG [60.5 vs 22.3, p = 0.011], but not in psoriasis. Caspase 3 and CD68 overexpression in skin biopsies distinguished EN/PG from psoriasis and controls. Upregulation of TNFα/NFκB in EN and PG is compatible with the efficacy of anti-TNF in EIM management. Data on overexpressed STAT3, but not MAdCAM1, support a rationale for JAK-inhibitors in EN and PG, while questioning the role of vedolizumab

Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis.

BACKGROUND & AIMS: Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE) and to provide end points for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patient assessments of disease severity. We also evaluated relationships between patient assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings. METHODS: We collected information from 186 patients with EoE in Switzerland and the United States (69.4% male; median age, 43 y) via surveys (n = 135), focus groups (n = 27), and semistructured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patient assessment of EoE severity. The PRO instrument was used prospectively in 153 adult patients with EoE (72.5% male; median age, 38 y), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 y). RESULTS: Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patient assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity (range, 0-10) and PRO score (range, 0-8.52) was 0.15. CONCLUSIONS: We developed and validated an EoE scoring system based on 7 PRO items that assess symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263

Small Bowel Bacterial Overgrowth is found in 71% of IBS patients and associated symptoms respond wel to Rifaximin in a phase IV trial

Background: The prevalence of small intestinal bowel bacterial overgrowth (SIBO) in patients with irritable bowel syndrome (IBS) ranges from 43% to 78% as determined by the lactulose hydrogen breath (LHBT) test. Although rifaximine, a non-absorbable antibiotic, has been able to decrease global IBS symptoms as well as bloating in placebo-controlled randomized trials, these results were not repeated in phase IV studies in daily clinical practice. Aim: To assess the prevalence of SIBO in an IBS cohort and to evaluate the treatment response in the IBS cohort affected by SIBO. Methods: Enrolled patients were diagnosed with IBS using the following criteria: fulfillment of the Rome III criteria, absence of alarm symptoms (anemia, weight loss, nocturnal symptoms etc), normal fecal calproectin, normal endoscopic workup including histology. Celiac disease was excluded by serology and/or duodenal biopsy. All patients underwent lactulose hydrogen breath testing (LHBT) for SIBO diagnosis. Patients with SIBO were treated with rifaximine tablets (400mg twice daily for 14 days). Both before and at week 6 after rifaximin treatment, patients completed a questionnaire, where the following criteria were assessed individually using 11-point Likert scales: the bloating, flatulence, abdominal pain, diarrhea, and overall well-being. Results: Hundred-fifty IBS patients were enrolled (76% female, mean age 44 ± 16 years), of whom 106 (71%) were diagnosed with SIBO and consequently treated with rifaximine. Rifaximine treatment significantly reduced the following symptoms as assessed by the symptom questionnaire: bloating (5.5 ± 2.6 before vs. 3.6 ± 2.7 after treatment, p <0.001), flatulence (5 ± 2.7 vs. 4 ± 2.7, p = 0.015), diarrhea (2.9 ± 2.4 vs. 2 ± 2.4, p = 0.005), abdominal pain (4.8 ± 2.7 vs. 3.3 ± 2.5, p <0.001) and resulted in improved overall well-being (3.9 ± 2.4 vs. 2.7 ± 2.3, p <0.001). Thirteen of the 106 treated patients were lost to follow-up (12%). The LHBT was repeated 2-4 weeks after rifaximine treatment in 65/93 (70%) patients. Eradication of SIBO was documented in 85% of all patients (55/65), whereas 15% of patients (10/65) tested positive for SIBO as determined by the LHBT testing. Conclusions: The results of our phase IV trial indicate that a high proportion of IBS patients tested positive for SIBO. IBS symptoms (bloating, flatulence, diarrhea, pain, overall well-being) were significantly diminished following a 2-week treatment with rifaximine. These results support the previous findings of randomized controlled trials that the presence of SIBO is associated with symptom generation in IBS patients and that reduction and/or elimination of SIBO may help to alleviate IBSassociated symptoms