Multinational evaluation of clinical decision-making in the treatment and management of mild-to-moderate ulcerative colitis.

OBJECTIVES: To understand current thinking and clinical decision-making in the treatment and management of patients with mild-to-moderate ulcerative colitis (UC). METHODS: This multinational, survey-based study was conducted in 2021. Two meetings were held, involving 11 IBD specialists, that used a series of questions and discussion to identify all factors possibly related to the management of UC. The importance of identified factors was assessed using an online questionnaire covering three scenarios - active disease, remission and patient empowerment. Each factor was scored on a scale of 0 (very-unimportant) to 100 (very-important) within each scenario, by a separate group of healthcare professionals working in IBD. RESULTS: A total of 157 individual factors were identified by the 11 IBD specialists and scored in the three scenarios by 56 respondents (52; 93% specialist gastroenterologists) from Europe and North America (25; 45%), South America (19; 34%) and the Middle East, Asia and Australia (12; 21%). For all scenarios, factors related to educating patients regarding UC and its treatment and understanding of patient goals ranked highest, ahead of clinical considerations regarding disease activity and treatment history. Setting realistic short-term treatment targets was a key consideration. 5-ASA optimisation and use of faecal calprotectin monitoring were core strategies across the three scenarios tested. Support for patients during longer-term management of their disease, starting from initial flare, was an important recurring theme. CONCLUSION: The current management approach for mild-to-moderate UC was found to be guided primarily by the patient's perspectives and goals, alongside assessment of their medical and disease history.

[Biologics in inflammatory bowel diseases]. / Biologika bei chronisch-entzündlichen Darmerkrankungen.

BACKGROUND: In addition to conventional anti-inflammatory treatment for chronic inflammatory bowel disease (IBD), there has been an evolution of new treatment options over the past 20 years. Already approved biologics provide multiple treatment alternatives but also make the treatment algorithms more complex. This development results in a substantial improvement in patient care. The ambitious treatment targets are associated with a higher quality of life and the reduction of long-term disability and morbidity. OBJECTIVE: The aim of this article is to give an overview of how biologics can currently be implemented in IBD. In particular, the current clinical management is presented and an outlook on future treatment options with biologics for IBD is provided. MATERIAL AND METHODS: A search was carried out in PubMed and ClinicalTrials.gov and the current German and European guidelines and expert recommendations were evaluated. RESULTS: Since the late 1990s there have been a continuously increasing number of treatment options for IBD. All substances have proven safety and efficacy in large randomized clinical studies and enable increasingly more individualized treatment for patients with IBD. Biologics are currently the standard treatment of choice for moderate to severe inflammatory activity as well as for steroid-refractory or steroid-dependent courses of disease after failure of conventional treatment. CONCLUSION: The diversity of IBD treatment offers increasing treatment options and thus improved patient care; however, as the number of new substances increases treatment becomes more complex. This article summarizes the current and future treatment options for IBD and their integration into current treatment algorithms.

Indirect comparison of vedolizumab and adalimumab for biologic-naive patients with ulcerative colitis.

AIM: Indirect comparison of efficacy and safety of vedolizumab with adalimumab in biologic-naïve patients with moderate to severe ulcerative colitis (UC). METHODS: Vedolizumab is a gut-selective medication for moderate to severe UC. Since no comparative trials are available for direct comparison of vedolizumab vs adalimumab in UC, a systematic review of literature databases was conducted to identify randomized, placebo-controlled trials of the two drugs in patients with moderate to severe UC after failure of conventional treatment. Studies were screened for eligibility by two reviewers based on predefined inclusion criteria. Bucher's adjusted indirect comparison was used to compare vedolizumab and adalimumab indirectly through placebo as common comparator. RESULTS: One vedolizumab study (GEMINI 1) and three adalimumab studies (ULTRA 1, ULTRA 2 and M10-447) met the eligibility criteria. Baseline characteristics of the included populations were similar in biologic-naïve UC patients across study arms. Although no statistically significant differences between treatments were found for induction efficacy endpoints, there was a trend toward a benefit of vedolizumab over adalimumab. There were also no significant differences between treatments for any maintenance efficacy endpoints, with no clear trend favoring either agent. Vedolizumab exhibited statistically superior maintenance safety compared with adalimumab, with significant reductions in risks of adverse events (relative risk 0.67 [95% confidence interval 0.57-0.80]; p < .0001), serious adverse events (0.20 [0.09-0.42]; p < .0001) and adverse events leading to discontinuation (0.14 [0.05-0.43]; p = .0006). CONCLUSION: This analysis indicates that vedolizumab has comparable efficacy to adalimumab with improved safety in biologic-naïve patients with moderate to severe UC.

Modelling the benefits of an optimised treatment strategy for 5-ASA in mild-to-moderate ulcerative colitis.

OBJECTIVES: 5-aminosalicylate (mesalazine; 5-ASA) is an established first-line treatment for mild-to-moderate ulcerative colitis (UC). This study aimed to model the benefits of optimising 5-ASA therapy. METHODS: A decision tree model followed 10 000 newly diagnosed patients with mild-to-moderately active UC through induction and 1 year of maintenance treatment. Optimised treatment (maximising dose of 5-ASA and use of combined oral and rectal therapy before treatment escalation) was compared with standard treatment (standard doses of 5-ASA without optimisation). Modelled data were derived from published meta-analyses. The primary outcomes were patient numbers achieving and maintaining remission, with an analysis of treatment costs for each strategy conducted as a secondary outcome (using UK reference costs). RESULTS: During induction, there was a 39% increase in patients achieving remission through the optimised pathway without requiring systemic steroids and/or biologics (6565 vs 4725 for standard). Potential steroidal/biological adverse events avoided included: seven venous thromboembolisms and eight serious infections. Out of the 6565 patients entering maintenance following successful induction on 5-ASA, there was a 21% reduction in relapses when optimised (1830 vs 2311 for standard). This translated into 297 patients avoiding further systemic steroids and 214 biologics. Optimisation led to an average net saving of £272 per patient entering the model for the induction and maintenance of remission over 1 year. CONCLUSION: Modelling suggests that optimising 5-ASA therapy (both the inclusion of rectal 5-ASA into a combined oral and rectal regimen and maximisation of 5-ASA dose) has clinical and cost benefits that supports wider adoption in clinical practice.

Galectin-2 suppresses contact allergy by inducing apoptosis in activated CD8+ T cells.

Galectins, a family of structurally related beta-galactoside-binding proteins, are expressed by various cells of the immune systems and seem to be important for the regulation of immune responses and immune cell homeostasis. Since it has been demonstrated that galectin-2 regulates cell-mediated inflammatory bowel disease and colitis in mice, we intended to investigate the role of galectin-2 in inflammatory cutaneous T cell-mediated immune responses. To address this issue, groups of naive mice were sensitized to the contact allergen 2,4-dinitro-1-fluorobenzene and systemically treated with galectin-2 to analyze the effects of galectin-2 on contact allergy. Here we show that galectin-2 is expressed in murine skin and is up-regulated upon cutaneous inflammation. Interestingly, treatment of mice with galectin-2 significantly reduced the contact allergy response. This effect was long-lasting since rechallenge of galectin-2-treated mice after a 14-day interval still resulted in a decreased ear swelling. We were able to demonstrate that galectin-2 induced a reduction of MHC class I-restricted immune responses in the treated animals, which was mediated by the induction of apoptosis specifically in activated CD8(+) T cells. Additionally, we report that the galectin-2-binding protein CD29 is up-regulated on the surface of activated CD8(+) T cells compared with naive CD8(+) T cells or CD4(+) T cells, suggesting that increased galectin-2/CD29 signaling might be responsible for the proapoptotic effects of galectin-2 on activated CD8(+) T cells. Taken together, these data indicate that galectin-2 may represent a novel therapeutic alternative for the treatment of CD8-mediated inflammatory disorders such as contact allergy.

Use of granulocyte/monocytapheresis in ulcerative colitis: A practical review from a European perspective.

Half of the patients with ulcerative colitis require at least one course of systemic corticosteroids in their lifetime. Approximately 75% of these patients will also require immunosuppressive drugs (i.e., thiopurines or biological agents) in the mid-term to avoid colectomy. Immunosuppressive drugs raise some concerns due to an increased risk of serious and opportunistic infections and cancer, particularly in elderly and co-morbid patients, underlining the unmet need for safer alternative therapies. Granulocyte/monocytapheresis (GMA), a CE-marked, non-pharmacological procedure for the treatment of ulcerative colitis (among other immune-mediated diseases), remains the only therapy targeting neutrophils, the hallmark of pathology in ulcerative colitis. GMA has proven its efficacy in different clinical scenarios and shows an excellent and unique safety profile. In spite of being a first line therapy in Japan, GMA use is still limited to a small number of centres and countries in Europe. In this article, we aim to give an overview from a European perspective of the mechanism of action, recent clinical data on efficacy and practical aspects for the use of GMA in ulcerative colitis.

Chronic intestinal failure and short bowel syndrome in Crohn's disease.

Chronic intestinal failure (CIF) is a rare but feared complication of Crohn's disease. Depending on the remaining length of the small intestine, the affected intestinal segment, and the residual bowel function, CIF can result in a wide spectrum of symptoms, from single micronutrient malabsorption to complete intestinal failure. Management of CIF has improved significantly in recent years. Advances in home-based parenteral nutrition, in particular, have translated into increased survival and improved quality of life. Nevertheless, 60% of patients are permanently reliant on parenteral nutrition. Encouraging results with new drugs such as teduglutide have added a new dimension to CIF therapy. The outcomes of patients with CIF could be greatly improved by more effective prevention, understanding, and treatment. In complex cases, the care of patients with CIF requires a multidisciplinary approach involving not only physicians but also dietitians and nurses to provide optimal intestinal rehabilitation, nutritional support, and an improved quality of life. Here, we summarize current literature on CIF and short bowel syndrome, encompassing epidemiology, pathophysiology, and advances in surgical and medical management, and elucidate advances in the understanding and therapy of CIF-related complications such as catheter-related bloodstream infections and intestinal failure-associated liver disease.

Mesalamine once daily is more effective than twice daily in patients with quiescent ulcerative colitis.

BACKGROUND & AIMS: Oral mesalamine (5-aminosalicylate) is the current standard of care for mild-to-moderate ulcerative colitis. We investigated the efficacy and safety of once daily administration of prolonged-release mesalamine granules in maintenance of remission in patients with quiescent ulcerative colitis, compared with the well established twice daily dosing regimen. METHODS: In this multicenter, randomized, single blind, noninferiority trial, 362 patients with quiescent ulcerative colitis were randomly assigned (1:1) to groups that were given oral mesalamine 2 g, once daily, or 1 g, twice daily, for 12 months. The primary objective was to compare remission rates at 1 year, based on the ulcerative colitis disease activity index score, using Kaplan-Meier methodology. RESULTS: At 1 year, 70.9% of the group given 2 g mesalamine once daily remained in remission vs 58.9% of the group given 1 g mesalamine twice daily; this difference was statistically significant (P = .024), indicating the increased efficacy of once daily, compared with twice daily, dosing. Self-reported adherence to therapy, measured by visual analog scale score after 4, 8, and 12 months, was significantly greater in the group given 2 g mesalamine once daily, compared with twice daily, at all but 1 study visit (P < .05). Compliance measured by medication taken was not significantly different between the groups. The difference between the 2 groups in overall incidence of adverse events was not statistically significant (P = .23). CONCLUSIONS: Patients with ulcerative colitis given prolonged-release oral mesalamine 2 g once daily had better remission rates, acceptability, and self-reported adherence to therapy compared with patients given oral mesalamine 1 g twice daily.

Management of inflammatory bowel diseases during pregnancy.

Inflammatory bowel diseases (IBD) have a high prevalence in younger patients with child-bearing potential. Usually, pregnancies in women with IBD will develop normally, if the patient is in remission or has minor disease activity at the time of conception. In contrast, the frequency of normal pregnancies is significantly reduced and the frequency of adverse outcomes like preterm birth or miscarriage is increased, when conception occurs in phases with active IBD. Therefore, it is generally recommended to women with IBD to conceive at a time with minor disease activity or in remission. IBD patients who plan to become pregnant or are pregnant should be treated adequately. Currently, it is widely accepted that the treatment of IBD with corticosteroids and 5-ASA derivatives does not increase the risk of malformations or adverse outcomes in pregnant IBD patients. However, a slight increase in the number of pre-term deliveries or reduced birth weight is observed. More recently, it has also been appreciated that azathioprine and 6-MP and presumably also infliximab and other TNF-alpha blockers can be safely used during pregnancy in IBD, as no significant increase of malformations, miscarriages or adverse pregnancy outcomes is observed. Information on cyclosporine and tacrolimus during pregnancy is scarcer, but it may be continued or started in some situations if clinically needed. Methotrexate is contraindicated, as this drug is known to significantly increase the risk of malformations and spontaneous abortion. Patients, who wish to nurse their babies, may be treated with steroids and 5-ASA derivatives without a significantly increased risk for the newborn.

Galectin-2 induces apoptosis of lamina propria T lymphocytes and ameliorates acute and chronic experimental colitis in mice.

Galectins have recently emerged as central regulators of the immune system. We have previously demonstrated that carbohydrate-dependent binding of galectin-2 induces apoptosis in activated T cells. Here, we investigate the potential therapeutic effect of galectin-2 in experimental colitis. Galectin-2 expression and its binding profile were determined by immunohistochemistry. Acute and chronic colitis was induced by dextran sodium sulfate administration and in a T-cell transfer colitis model. Apoptosis was assessed by TdT-mediated dUTP-biotin nick-end labeling, and cytokine secretion was determined by cytometric bead array. We show that galectin-2 was constitutively expressed mainly in the epithelial compartment of the mouse intestine and bind to lamina propria mononuclear cells. During colitis, galectin-2 expression was reduced, but could be restored to normal levels by immunosuppressive treatment. Galectin-2 treatment induced apoptosis of mucosal T cells and thus ameliorated acute and chronic dextran-sodium-sulfate-induced colitis and in a T-helper-cell 1-driven model of antigen-specific transfer colitis. Furthermore, the pro-inflammatory cytokine release was inhibited by galectin-2 treatment. In preliminary toxicity studies, galectin-2 was well tolerated. Our study provides evidence that galectin-2 induces apoptosis in vivo and ameliorates acute and chronic murine colitis. Furthermore, galectin-2 has no significant toxicity over a broad dose range, suggesting that it may serve as a new therapeutic agent in the treatment of inflammatory bowel disease.

Epithelial restitution and wound healing in inflammatory bowel disease.

Inflammatory bowel disease is characterized by a chronic inflammation of the intestinal mucosa. The mucosal epithelium of the alimentary tract constitutes a key element of the mucosal barrier to a broad spectrum of deleterious substances present within the intestinal lumen including bacterial microorganisms, various dietary factors, gastrointestinal secretory products and drugs. In addition, this mucosal barrier can be disturbed in the course of various intestinal disorders including inflammatory bowel diseases. Fortunately, the integrity of the gastrointestinal surface epithelium is rapidly reestablished even after extensive destruction. Rapid resealing of the epithelial barrier following injuries is accomplished by a process termed epithelial restitution, followed by more delayed mechanisms of epithelial wound healing including increased epithelial cell proliferation and epithelial cell differentiation. Restitution of the intestinal surface epithelium is modulated by a range of highly divergent factors among them a broad spectrum of structurally distinct regulatory peptides, variously described as growth factors or cytokines. Several regulatory peptide factors act from the basolateral site of the epithelial surface and enhance epithelial cell restitution through TGF-beta-dependent pathways. In contrast, members of the trefoil factor family (TFF peptides) appear to stimulate epithelial restitution in conjunction with mucin glycoproteins through a TGF-beta-independent mechanism from the apical site of the intestinal epithelium. In addition, a number of other peptide molecules like extracellular matrix factors and blood clotting factors and also non-peptide molecules including phospholipids, short-chain fatty acids (SCFA), adenine nucleotides, trace elements and pharmacological agents modulate intestinal epithelial repair mechanisms. Repeated damage and injury of the intestinal surface are key features of various intestinal disorders including inflammatory bowel diseases and require constant repair of the epithelium. Enhancement of intestinal repair mechanisms by regulatory peptides or other modulatory factors may provide future approaches for the treatment of diseases that are characterized by injuries of the epithelial surface.

European Crohn's and Colitis Organisation Topical Review on Prediction, Diagnosis and Management of Fibrostenosing Crohn's Disease.

This ECCO topical review of the European Crohn's and Colitis Organisation [ECCO] focused on prediction, diagnosis, and management of fibrostenosing Crohn's disease [CD]. The objective was to achieve evidence-supported, expert consensus that provides guidance for clinical practice.

Modulation of gastrointestinal wound repair and inflammation by phospholipids.

The mucosal surface of the digestive tract is a critical barrier between a broad spectrum of noxious and immunogenic substances present in the gastrointestinal lumen and the underlying mucosal immune system. Its preservation following various forms of injury or physiological damage is essential to prevent the invasion of harmful luminal factors into the host, which subsequently may lead to inflammation, uncontrolled immune response, and a disequilibrium of the homeostasis of the host. The preservation of this barrier following injuries is regulated by a broad spectrum of structurally distinct regulatory molecules, including phospholipids. Phospholipids play a pivotal role in the modulation of intestinal inflammation. They have been demonstrated to both promote and inhibit inflammation, and their overall impact in an individual setting seems to be dependent on several factors, including the level of immune cell activation and the presence of other mediators. Modulation of lipid mediators through administration of lysophosphatidic acid (LPA) or lisofylline (LSF), inhibitors of phospholipase A2 (PLA2) biosynthesis or monoclonal antibodies against thromboxane (TBX) or platelet-activating factor (PAF) as a therapeutic approach have been used in several models of inflammation; however, beneficial effects were not always convincing and further studies are warranted.

Anaemia in the Elderly IBD Patient.

OPINION STATEMENT: Anaemia is a common multifactorial extraintestinal manifestation in IBD patients. Moreover, anaemia represents an important health problem among the elderly population and has a significant impact on healthcare utilisation and costs. Data on the prevalence, diagnosis and management of anaemia in elderly IBD patients are scarce, since clinical trials have largely excluded this population. In this review, we reconsider anaemia in older IBD patients in the light of new diagnostic and therapeutic tools.

Reduced incidence of esophageal lesions by luminal esophageal temperature-guided second-generation cryoballoon ablation.

BACKGROUND: An increased incidence of esophageal lesions (EL) after pulmonary vein isolation (PVI) using the second-generation cryoballoon (CB2) has been described. We hypothesized that luminal esophageal temperature (LET)-guided PVI reduces the incidence of EL. OBJECTIVE: The aim of this study was to investigate the incidence of EL after LET-guided PVI using the CB2. METHODS: Ninety-four consecutive patients underwent CB2-PVI for paroxysmal or persistent atrial fibrillation. Target freezing time was 2 × 240 seconds. LET was continuously measured by a probe with 3 thermocouples. Early freezing interruption was performed when LET reached a prespecified cutoff temperature. A group of 32 patients who underwent CB2-PVI with observational LET measurement served as the control group. Postprocedural esophagoscopy was performed in all patients. RESULTS: Compared with observational LET measurement, a strategy of LET-guided CB-PVI significantly reduced the incidence of EL from 18.8% to 3.2% (P = .008). A progressive decline in the incidence of EL was observed with an increasing LET cutoff: 7.1% (2/28 patients, 12°C cutoff) and 1.5% (1/66 patients, 15°C cutoff, P = .005 vs control). Despite early freezing interruption at a single pulmonary vein in 27% (25/94) of patients, complete PVI was achieved in all patients using the 28 mm balloon. Repeat esophagoscopy confirmed healing of EL after 1 week. After a mean of 268 ± 119 days, 87% (76/87) of patients were free of recurrent atrial fibrillation or atrial tachycardia following a 90-days blanking period. CONCLUSION: LET-guided CB2-PVI significantly reduced the incidence of thermal EL. Interrupting cryoablation at 15°C LET was associated with the lowest incidence of esophageal injury.

Current biological therapies for inflammatory bowel disease.

Current biological therapies for inflammatory bowel disease reflect the exponential advancement in understanding the human intestinal immune system and particularly the biology of intestinal inflammation over the past decade. The better understanding of the mechanisms of inflammatory bowel disease has evolved from descriptive clinical data and genetically engineered animal models. It led to great interest in a variety of new therapeutic agents and procedures with novel actions. This review will discuss the mechanisms of biologics (antibodies against pro-inflammatory cytokines, T-cell antibodies, anti-inflammatory cytokines, adhesion molecule blockers, growth factors, colony stimulating factors, fusion proteins, anti-sense oligonucleotides, hormones, immunostimulatory DNA (ISS-DNA, CpG Oligodeoxynucleotides) and parasites (Trichuris suis eggs), used in inflammatory bowel disease and summarize the available data on investigational and approved agents, and briefly touch on probiotics and extracorporeal immunomodulation (leukocyte apheresis and photoapheresis). Based on the data discussed, it appears that biologics may play an increasing role in managing inflammatory bowel disease in the near future.