Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials.

BACKGROUND: There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. METHODS: This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16-75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5-9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH). FINDINGS: Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p<0·0001; adjusted treatment difference 21·6% [95% CI 15·8-27·4] for UC1 and 29·0% [23·2-34·7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 [42%] of 148; 30 mg 80 [52%] of 154) than those receiving placebo (18 [12%] of 149; p<0·0001; adjusted treatment difference 30·7% [21·7-39·8] for upadacitinib 15 mg vs placebo and 39·0% [29·7-48·2] for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 [5%] of 319 in the upadacitinib 45 mg group vs six [4%] of 155 in the placebo group), creatine phosphokinase elevation (15 [4%] vs three [2%]), and acne (15 [5%] vs one [1%]). In UC2, the most frequently reported adverse event was acne (24 [7%] of 344 in the upadacitinib 45 mg group vs three [2%] of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight [3%] vs nine (6%) in UC1 and 11 [3%] vs eight [5%] in UC2; adverse events leading to discontinuation six [2%] vs 14 [9%] in UC1 and six [2%] vs nine [5%] in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 [13%] of 148 in the upadacitinib 15 mg group vs 11 [7%] of 154 in the upadacitinib 30 mg group vs 45 [30%] of 149 in the placebo group), nasopharyngitis (18 [12%] vs 22 [14%] vs 15 [10%]), creatine phosphokinase elevation (nine [6%] vs 13 [8%] vs three [2%]), arthralgia (nine [6%] vs five [3%] vs 15 [10%]), and upper respiratory tract infection (seven [5%] vs nine [6%] vs six [4%]). The proportion of serious adverse events (ten [7%] vs nine [6%] vs 19 [13%]) and adverse events leading to discontinuation (six [4%] vs ten [6%] vs 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths. INTERPRETATION: Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis. FUNDING: AbbVie.

Efficacy of Induction Therapy With Calcineurin Inhibitors in Combination With Ustekinumab for Acute Severe Ulcerative Colitis.

Ulcerative colitis is a chronic inflammatory bowel disease. Approximately 20% of patients experience an acute severe attack during their life. In acute severe ulcerative colitis (ASUC), first-line therapy is intravenous (IV) steroids. In the absence of clinical improvement, 2 medical options can be considered: ciclosporin or infliximab.1 In ASUC, ciclosporin is commonly used as a bridging therapy for thiopurines. Pellet et al2 found that the same bridge strategy with vedolizumab was effective and can avoid colectomy. Given that an increasing number of patients with ASUC have been exposed to thiopurines, vedolizumab, and anti-tumor necrosis factor biologic therapies, newer approaches are needed in these patients, such as tofacitinib or ustekinumab. Ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, has shown efficacy in ulcerative colitis and can be given in this indication.3 In this retrospective study, we evaluate the efficacy and safety of a bridge from calcineurin inhibitor to ustekinumab in patients with ASUC.

Technical feasibility, clinical effectiveness, and safety of esophageal stricture dilation using a novel endoscopic attachment cap in adults with eosinophilic esophagitis.

BACKGROUND AND AIMS: The BougieCap (Ovesco Endoscopy AG, Tübingen, Germany) is a new device that allows optical and tactile feedback during stricture dilation of the upper GI tract. We evaluated the technical feasibility, clinical efficacy, and safety of a 1-time esophageal stricture dilation using the BougieCap in adults with eosinophilic esophagitis (EoE). METHODS: EoE patients prospectively included in the Swiss EoE Cohort were dilated with the BougieCap for esophageal strictures (esophageal diameter, ≤14 mm) and stricture-related symptoms. Symptoms were assessed before and 2 weeks after a single dilation session using the validated Eosinophilic Esophagitis Activity Index Patient Reported Outcomes instrument (score ranges from 0 to 100 points). RESULTS: Fifty patients (70% men; median age, 41 years; median disease duration, 4 years; 50% treated with swallowed topical corticosteroids, 10% with proton pump inhibitors, 14% with combined swallowed topical corticosteroids plus proton pump inhibitors, 14% with elimination diet, 12% without antieosinophil therapy) were evaluated. Endoscopic bougienage was technically successful in 100%. The median esophageal diameter increased from 12 mm (interquartile range [IQR], 12-13) to 16 mm (IQR, 16-16; P < .001). Median symptom severity dropped from 32 points (IQR, 27-41) to 0 (IQR, 0-10; P < .001) at 2 weeks postdilation. In 1 patient the BougieCap was temporarily lost after stricture dilation in the hypopharynx but could be retrieved. No severe adverse events were reported. CONCLUSIONS: In adults with EoE, endoscopic treatment of esophageal strictures using the BougieCap is technically feasible and safe and offers significant symptomatic improvement in the short term.

Risk of Vaccine-Preventable Infections in Swiss Adults with Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) have a higher risk of infection and are frequently not up to date with their immunizations. OBJECTIVES: This study aims to review vaccination status and evaluate whether age, disease type, or treatment regimen could predict the absence of seroprotection against selected vaccine-preventable infection in adults with IBD. METHODS: Cross-sectional study using questionnaire, immunization records review, and assessment of tetanus-specific, varicella-specific, and measles-specific immunoglobulin G concentrations. ClinicalTrials.gov: NCT01908283. RESULTS: Among the 306 adults assessed (median age 42.7 years old, 70% with Crohn's disease, 78% receiving immunosuppressive treatment), only 33% had an immunization record available. Absence of seroprotection against tetanus (6%) was associated with increasing age and absence of booster dose; absence of seroprotection against varicella (1%) or measles (3%) was exclusively observed in younger patients with Crohn's disease. There was no statistically significant difference in immunoglobulin concentrations among treatment groups. Although vaccinations are strongly recommended in IBD patients, the frequencies of participants with at least 1 dose of vaccine recorded were low for nearly all antigens: tetanus 94%, diphtheria 87%, pertussis 54%, poliovirus 22%, measles-mumps-rubella 47%, varicella-zoster 0%, Streptococcus pneumoniae 5%, Neisseria meningitidis 12%, hepatitis A 41%, hepatitis B 48%, human papillomavirus 5%, and tick-borne encephalitis 6%. CONCLUSIONS: Although many guidelines recommend the vaccination of IBD patients, disease prevention through immunization is still often overlooked, including in Switzerland, increasing their risk of vaccine-preventable diseases. Serological testing should be standardized to monitor patients' protection during follow-up as immunity may wane faster in this population.

[Cough from the perspective of a gastroenterologist]. / Husten aus gastroenterologischer Sicht.

Cough from the perspective of a gastroenterologist Abstract. Chronic cough can have numerous origins. The work-up of these conditions should always include a multidisciplinary approach to exclude other causes first (cardial, pulmonary, structural changes of pharynx and larynx, allergies, malignancy) before thinking of an upper GI pathology. Cough as an extra-esophageal manifestation of gastroesophageal reflux disease (GERD) is the most common gastroenterological condition. From a gastroenterologist's perspective eosinophilic esophagitis (EoE) and esophageal motility disorders are potential differential diagnosis. If other worrisome symptoms (weight loss, anemia, dysphagia) are present at the same time an endoscopic evaluation with esophago-gastro-duodenoscopy (EGD) should be performed first to exclude a malignancy. Hereby one should perform biopsies of the esophagus to exclude an eosinophilic esophagitis (EoE). If the macroscopic and histopathology results of the EGD are unremarkable a probatory trial of acid-suppressive therapy with proton pump inhibitors (PPIs) is the first-line therapeutic option. For non-responders to PPI-therapy functional diagnostics are the next step. With the help of ambulatory pH-impedance monitoring one can diagnose a non- erosive reflux disease and an esophageal hypersensitivity. An esophageal manometry can deliver relevant information about the physiological anti-reflux barrier and diagnose motility disorders of the esophagus. Surgical therapy (antireflux surgery) can be an option for selected patients with proven reflux associated cough refractory to medical therapy. The aim of this review is to give an overview over a possible diagnostic-therapeutic algorithm from a gastroenterologist's point of view to approach the symptom cough.

Association of Alterations in Intestinal Microbiota With Impaired Psychological Function in Patients With Inflammatory Bowel Diseases in Remission.

BACKGROUND & AIMS: Depression and anxiety are frequent comorbidities with inflammatory bowel diseases (IBD). Alterations to the intestinal microbiome promote not only intestinal inflammation but also psychologic function. We studied the interactions between the composition of the intestinal microbiota and psychological outcomes in patients with IBD in Switzerland. METHODS: We performed a prospective study of psychological comorbidities and quality of life (QoL) in 171 participants in the Swiss IBD Cohort Study with IBD in remission. Participants complete the Hospital Anxiety and Depression Scale, Perceived Stress Questionnaire, the 36-Item Short Form Survey, and the IBD QoL Questionnaire. Microbes were collected from intestinal biopsies and analyzed by 16S rRNA high-throughput sequencing. RESULTS: Microbiomes of patients with higher perceived stress had significantly lower alpha diversity. Anxiety and depressive symptoms were significantly associated with beta diversity. We found a negative correlation between psychological distress and abundance of Clostridia, Bacilli, Bacteroidia, and Beta- and Gamma-proteobacteria. Psychological distress was also associated with decreases in operational taxonomic units from the lineages of Lachnospiraceae, Fusobacteriaceae, Ruminococcaceae, Veillonellaceae, Alcaligenaceae, Desulfovibrionaceae, and Bacteroidaceae families. The relative abundance of Bifidobacterium in patients with Crohn's disease and Desulfovibrio in patients with ulcerative colitis correlated with depression, whereas abundance of Sutterella, RF 32, and Lactococcus correlated with quality of life in patients with Crohn's disease. CONCLUSIONS: We identified correlations between the composition of the intestinal microbiota in patients with IBD and remission, psychological well-being, and QoL. Further studies should investigate how intestinal inflammation, the microbiome, and microbial metabolites affect psychological well-being and whether these components are mono- or bi-directionally linked.

Emerging Treatment Options in Inflammatory Bowel Disease: Janus Kinases, Stem Cells, and More.

BACKGROUND: Treatment of inflammatory bowel diseases (IBD) has tremendously improved during the last 20 years; however, a substantial fraction of patients does not respond to available therapies or lose response, and new strategies are needed. SUMMARY: Two pharmacological principles have been successfully used for IBD treatment: inhibition of cellular signaling and interference with leukocyte trafficking. Besides tumor necrosis factor, interleukin (IL)-23 is a promising drug target, and antibodies for the combined inhibition of IL-23 and IL-12 (ustekinumab and briakinumab) or selective IL-23 inhibition (brazikumab, risankizumab, and mirikizumab) seem to be effective in Crohn's disease (CD) with emerging evidence also for ulcerative colitis (UC). Janus kinase (JAK) mediates intracellular signaling of a large number of cytokines. Tofacitinib is the first JAK inhibitor approved for UC, and the JAK inhibitors filgotinib and upadacitinib showed potential in CD. Leukocyte trafficking can be inhibited by interference with lymphocyte integrin-α4ß7 or endothelial MadCAM-1. The α4ß7 integrin inhibitor vedolizumab is an established treatment in IBD, and long-term data of pivotal studies are now available. Additional molecules with therapeutic potential are α4ß7-specific abrilumab, ß7-specific etrolizumab, and the α4-specific small molecule AJM300. PF-00547659, an antibody against endothelial MadCAM-1, also showed therapeutic potential in UC. Modulation of sphingosine-1-phosphate receptor (S1PR) activity is necessary for the egress of lymphocytes into the circulation, and S1PR modulation results in lymphocyte trapping in lymphatic organs. Ozanimod, an S1PR1 and S1PR5 inhibitor, has been successfully tested in initial studies in UC. Mesenchymal stem cell therapy has been approved for the treatment of complex, active CD fistula, and mesenchymal stem cell therapy might be a paradigm shift for this condition. Autologous stem cell transplantation (ASCT) has been successfully used in CD case series; however, in a randomized trial, a highly stringent endpoint was not met. However, considering positive effects in secondary endpoints, ASCT might be a future treatment of last resort in severe, refractory CD cases, provided that safer protocols can be provided. Key messages: New IBD treatments are successful for a significant fraction of patients. However, new strategies for patient selection, treatment combinations, and/or additional therapies must be developed to serve the need of all IBD patients.

Therapies in Inflammatory Bowel Disease Patients with Extraintestinal Manifestations.

Extraintestinal manifestations (EIM) have become an important source of morbidity and disability as well as an identified risk factor for an unfavorably course of disease in inflammatory bowel diseases (IBD). Therefore, efforts have been put into a more global and interdisciplinary management of IBD patients in collaboration with rheumatologists, dermatologists, and ophthalmologists. A real therapeutic success has also been obtained with a more "systemic" IBD treatment associated with the development of monoclonal antibodies against TNF alpha and biological agents derived from the treatment of rheumatological disease (also called biological Disease-Modifying Antirheumatic Drugs). The prevalence of these EIM remains too low to undergo randomized controlled trials with this specific focus and therefore the evidence relies on case series and experts' opinions, which lowers the level of evidence. After a careful review of the most recent literature, this paper aims to update the reader on the latest therapeutic management of IBD patients with EIM.

TNF-Alpha Blockers in Inflammatory Bowel Diseases: Practical Recommendations and a User's Guide: An Update.

BACKGROUND: Anti-tumour necrosis factor-alpha (anti-TNF) antagonists have been the mainstay in the treatment of inflammatory bowel diseases (IBDs) for over 20 years. SUMMARY: This review article aimed to provide an update on recent advances in TNF antagonist therapy for IBDs. Key Messages: Their position in the treatment algorithm has evolved to "rapid step-up therapy" or "top-down therapy" according to disease severity and patients' characteristics. Limitations of anti-TNF antagonists include loss of response in up to 30-50% of patients with or without the development of antibodies. Therapeutic drug monitoring should provide a tailored, personalized approach to this scenario. Recently, biosimilar agents have been approved for IBDs and are considered equivalent in efficacy to the originator.

Management of the Elderly Inflammatory Bowel Disease Patient.

Inflammatory bowel disease (IBD) is increasingly diagnosed among elderly persons (older than 60 years). Epidemiological studies show that late-onset IBD is characterized by predominance of colonic disease, milder disease course, and less frequent occurrence of extraintestinal manifestations. However, due to comorbidities, polypharmacy and reduced resistance to severe disease course elderly patients have an increased risk of mortality. Drug treatment generally follows the same algorithms as in the younger IBD patients. This is challenging for the treating physician as this population is usually underrepresented in clinical trials and treatment outcomes as well as safety data on the elderly population are scarce. Choice of drugs should consider risk of infections, skin cancer, lymphoma, and metabolic as well as cardiovascular side effects. Considering comorbidities, surgical interventions such as colectomy with ileo-anal pouch anastomosis for refractory ulcerative colitis can be performed safely provided that the anal sphincter function is adequately maintained. Special attention should be given in this age group to general health issues, including nutrition, vaccination, bone, muscle, and mental health as well as colorectal and skin cancer screening.

Therapeutic Drug Monitoring to Guide Clinical Decision Making in Inflammatory Bowel Disease Patients with Loss of Response to Anti-TNF: A Delphi Technique-Based Consensus.

BACKGROUND: Loss of response is frequently encountered in patients with inflammatory bowel disease (IBD) treated with antitumor necrosis factor (TNF) agents. Therapeutic drug monitoring (TDM) and antidrug antibody measurement are increasingly used in this setting. METHODS: To establish a consensus on the use of TDM in the context of loss of response to anti-TNFs, we performed a vote using a Delphi-style process followed by an expert panel discussion among 8 IBD specialists practicing in Switzerland, Europe. Statements were rated on an even Likert-scale ranging from 1 (strong disagreement) to 4 (strong agreement), based on expert opinion and the available literature. RESULTS: The experts agreed on the following statements: (i) loss of response is associated with inadequate drug levels in both Crohn's disease and ulcerative colitis; (ii) best timepoint for measuring drug levels is prior to the next application (= trough levels) with different thresholds for anti-TNF agents (infliximab 5 µg/mL, adalimumab 8 µg/mL, certolizumab pegol 10 µg/mL); (iii) antidrug antibodies are predictive for loss of response; and (iv) antidrug-antibody titers and drug trough levels are key determinants in the treatment algorithm. Data about non-anti-TNF biologics were considered too limited to propose recommendations. CONCLUSION: A Delphi-style consensus among 8 IBD experts shows that TDM and measurement of antidrug-antibody titers are useful in the context of loss of response to anti-TNF. Optimal cutoff levels depend on the type of anti-TNF. These values are critical in the decision making process. More studies are needed to address the value of such measurements for non-anti-TNF biologics.

High Immunogenicity of the Pneumococcal Conjugated Vaccine in Immunocompromised Adults With Inflammatory Bowel Disease.

INTRODUCTION: Patients with inflammatory bowel disease (IBD) are predisposed to pneumococcal infections due to their underlying disease and iatrogenic immunosuppression. Vaccination with the 13-valent pneumococcal conjugated vaccine (PCV13) is recommended, but with poor take-up and few data available. We performed an open-label, phase IV, multicenter study to evaluate the safety and immunogenicity of PCV13 in adults with IBD and to analyze the influence of immunomodulating treatments on anti-pneumococcal seroresponses. METHODS: We enrolled 306 patients with IBD from March 2014 through February 2016, with the following exclusion criteria: current IBD flare, pregnancy, pneumococcal immunization in the previous 5 years, and influenza immunization in the previous 4 weeks. PCV13 was administered intramuscularly. Serotype-specific vaccine responses were evaluated using an opsonophagocytic assay. Adverse events were monitored by diary cards and standardized phone interviews. RESULTS: The median seroprotection rate increased significantly from 43.9% (95% confidence interval [CI], 42.3-45.5) at inclusion to 90.4% (95% CI, 89.5-91.3%; P < 0.001) after vaccination. Patients receiving anti-tumor necrosis factor agents achieved a slightly lower seroprotection rate (from 44.5% [95% CI, 42.3%-46.8%] to 86.6% [95% CI, 84.9%-88.1%]) than patients treated with other types of immunosuppressive regimens (thiopurine, methotrexate, oral corticosteroids; from 44.7% [95% CI, 41.7%-47.7%] to 93.8% [95% CI, 92.1%-95.2%]) or nonimmunosuppressive treatment (5-aminosalicylate, topical corticosteroids, vedolizumab; from 41.3% [95% CI, 37.9%-44.8%] to 95.2% [95% CI, 93.4%-96.6%]). There were no safety issues. DISCUSSION: Overall, the administration of PCV13 was highly immunogenic and well tolerated, irrespective of the baseline treatment, and should be encouraged in all adults with IBD.

[The medical Therapy of inflammatory bowel diseases]. / Medikamentöse Behandlung der CED.

The medical Therapy of inflammatory bowel diseases Abstract. Since the introduction of biological therapy, using monoclonal antibodies, the management of inflammatory bowel disease has evolved a lot. However, the treatment concept of these two chronic, relapsing diseases (Crohn's disease and ulcerative colitis) remains the same: choosing the right medication for the induction of remission, based on the activity and extend of disease, and then pursue, ideally, with the same medication for the maintenance of remission. This article covers in a practical (algorithm) and concise way for the general practitioner and the GI specialist the basic and the more recent knowledge in the field.

[Smoking and digestive tract: a complex relationship. Part 1: Inflammatory bowel disease and cigarette smoking]. / Tabagisme et système digestif: une relation complexe. Partie 1: Maladies inflammatoires chroniques de l'intestin et consommation de tabac.

Little is known about the effects of smoking on inflammatory bowel diseases (IBD). However the co-occurrence of smoking and IBD often happens in ambulatory care. Smokers have a doubled risk of developing a Crohn's disease with a more active disease course. After quitting, a decrease in risk can be observed after only one year. An inverse relationship is found between smoking and ulcerative colitis. Smoking seems protective for the development of the disease and its course is less active among smokers. Smoking cessation transitorily increases the risk of developing ulcerative colitis. Nevertheless, continuing smoking cannot be justified among those patients given the risks of long-term extra-digestive effects. It is thus important to counsel all smokers with an IBD to quit smoking.

[Smoking and digestive tract: a complex relationship. Part 2: Intestinal microblota and cigarette smoking]. / Tabagisme et système digestif: une relation complexe. Partie 2: Microbiote intestinal et tabagisme.

The digestive tract is colonized from birth by a bacterial population called the microbiota which influences the development of the immune system. Modifications in its composition are associated with problems such as obesity or inflammatory bowel diseases. Antibiotics are known to influence the intestinal microbiota but other environmental factors such as cigarette smoking also seem to have an impact on its composition. This influence might partly explain weight gain which is observed after smoking cessation. Indeed there is a modification of the gut microbiota which becomes similar to that of obese people with a microbiotical profile which is more efficient to extract calories from ingested food. These new findings open new fields of diagnostic and therapeutic approaches through the regulation of the microbiota.

Bone health in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are prone to reduced bone mineral density and elevated overall fracture risk. Osteopenia affects up to 40% of patients with IBD (high regional variability). Besides disease activity, IBD specialists must consider possible side effects of medication and the presence of associated diseases and extraintestinal manifestations. Osteopenia and osteoporosis remain frequent problems in patients with IBD and are often underestimated because of widely differing screening and treatment practices. Malnutrition, chronic intestinal inflammation and corticosteroid intake are the major pathophysiological factors contributing to osteoporosis. Patients with IBD are screened for osteoporosis using dual-energy X-ray absorptiometry (DXA), which is recommended for all patients with a prolonged disease course of more than three months, with repeated corticosteroid administration, aged >40 years with a high FRAX risk score or aged <40 years with multiple risk factors. From a therapeutic perspective, besides good disease control, vitamin D supplementation and glucocorticoid sparing, several specific osteological options are available: bisphosphonates, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (denosumab), parathyroid hormone (PTH) analogues and selective estrogen receptor modulators. This review provides an overview of the pathophysiology, diagnosis, prevention and treatment of IBD-associated bone loss.

[Autoimmune hepatitis]. / Hépatite auto-immune.

Autoimmune hepatitis is a systemic disease, difficult to diagnose due the high variability of the clinical presentation and some non specific histological features. The recent identification of additional autoantibodies used as serological markers, as well as simplified diagnostic criteria should help the primary care physician to advance with the diagnostic process. These progresses are crucial as undiagnosed and therefore untreated autoimmune hepatitis has a poor prognosis, whereas immunosuppressive therapy leads to remission in a majority of cases.

Benchmarking microbial DNA enrichment protocols from human intestinal biopsies.

Shotgun metagenomic sequencing is a powerful tool for studying bacterial communities in their natural habitats or sites of infection, without the need for cultivation. However, low microbial signals in metagenomic sequencing can be overwhelmed by host DNA contamination, resulting in decreased sensitivity for microbial read detection. Several commercial kits and other methods have been developed to enrich bacterial sequences; however, these assays have not been tested extensively for human intestinal tissues yet. Therefore, the objective of this study was to assess the effectiveness of various wet-lab and software-based approaches for depleting host DNA from microbiome samples. Four different microbiome DNA enrichment methods, namely the NEBNext Microbiome DNA Enrichment kit, Molzym Ultra-Deep Microbiome Prep, QIAamp DNA Microbiome kit, and Zymo HostZERO microbial DNA kit, were evaluated, along with a software-controlled adaptive sampling (AS) approach by Oxford Nanopore Technologies (ONT) providing microbial signal enrichment by aborting unwanted host DNA sequencing. The NEBNext and QIAamp kits proved to be effective in shotgun metagenomic sequencing studies, as they efficiently reduced host DNA contamination, resulting in 24% and 28% bacterial DNA sequences, respectively, compared to <1% in the AllPrep controls. Additional optimization steps using further detergents and bead-beating steps improved the efficacy of less efficient protocols but not of the QIAamp kit. In contrast, ONT AS increased the overall number of bacterial reads resulting in a better bacterial metagenomic assembly with more bacterial contigs with greater completeness compared to non-AS approaches. Additionally, AS also allowed for the recovery of antimicrobial resistance markers and the identification of plasmids, demonstrating the potential utility of AS for targeted sequencing of microbial signals in complex samples with high amounts of host DNA. However, ONT AS resulted in relevant shifts in the observed bacterial abundance, including 2 to 5 times more Escherichia coli reads. Furthermore, a modest enrichment of Bacteroides fragilis and Bacteroides thetaiotaomicron was also observed with AS. Overall, this study provides insight into the efficacy and limitations of various methods for reducing host DNA contamination in human intestinal samples to improve the utility of metagenomic sequencing.

Machine Learning in Antibody Diagnostics for Inflammatory Bowel Disease Subtype Classification.

Antibody testing in inflammatory bowel disease (IBD) can add to diagnostic accuracy of the main subtypes Crohn's disease (CD) and ulcerative colitis (UC). Whether modern modeling techniques such as supervised and unsupervised machine learning are of value for finer distinction of subtypes such as IBD-unclassified (IBD-U) is not known. We determined the antibody profile of 100 adult IBD patients from the Swiss IBD cohort study with known subtype (50 CD, 50 UC) as well as of 76 IBD-U patients. We included ASCA IgG and IgA, p-ANCA, MPO- and PR3-ANCA, and xANCA measurements for computing different antibody panels as well as machine learning models. The AUC of an optimized antibody panel was 85% (95%CI, 78-92%) to distinguish CD from UC patients. The antibody profile of IBD-U patients was closely related to UC. No specific antibody profile was predictive for IBD-U nor for re-classification. The panel diagnostic was in favor of UC reclassification prediction with a correct assignment rate of 69.2-73.1% depending on the cut-off applied. Supervised machine learning could not distinguish between CD, UC, and IBD-U. More so, unsupervised machine learning suggested only two distinct clusters as a likely number of IBD subtypes. Antibodies in IBD are supportive in confirming clinical determined subtypes CD and UC but have limited capacity to predict IBD-U and reclassification during follow-up. In terms of antibody profiles, IBD-U is not a distinct subtype of IBD.

Swiss expert opinion: current approaches in faecal microbiota transplantation in daily practice.

INTRODUCTION: Faecal microbiota transplantation (FMT) is an established therapy for recurrent C. difficile infection, and recent studies have reported encouraging results of FMT in patients with ulcerative colitis. Few international consensus guidelines exist for this therapy, and thus FMT policies and practices differ among European countries. As of 2019, stool transplants are considered a non-standardised medicinal product in Switzerland, and a standardised production process requires authorisation by the Swiss Agency for Therapeutic Products. This authorisation leads to prolonged administrative procedures and increasing costs, which reduces treatment accessibility. In particular, patients with ulcerative colitis in Switzerland can only benefit from FMT off-label, even though it is a valid therapeutic option. Therefore, this study summarised the available data on FMT and established a framework for the standardised use of FMT. METHODS: A panel of Swiss gastroenterologists with a special interest in inflammatory bowel disease was established to identify the current key issues of FMT. After a comprehensive review of the literature, statements were formulated about FMT indications, donor screening, stool transplant preparation and administration, and safety aspects. The panel then voted on the statements following the Delphi process; the statements were reformulated and revoted until a consensus was reached. The manuscript was then reviewed by an infectiologist (the head of Lausanne's FMT centre). RESULTS: The established statements are summarised in the supplementary tables in the appendix to this paper. The working group hopes these will help standardise FMT practice in Switzerland and contribute to making faecal microbiota transplantation a safe and accessible treatment for patients with recurrent C. difficile infections and selected patients with ulcerative colitis, as well as other indications in the future.