Ustekinumab in the Treatment of Inflammatory Bowel Diseases: Evolving Paradigms.

Inflammatory bowel diseases, comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing, and remitting immune-mediated inflammatory diseases affecting the gastrointestinal tract. Ustekinumab (UST) is a monoclonal antibody that blocks the p40 subunit of the anti-interleukin (IL) 12/23. Pivotal trials (CERTIFI and UNITI-IM for CD, UNIFI for UC) established the efficacy of UST for the induction and maintenance of remission in both CD and UC, with the most favorable results in naïve patients to biologics. In recent years, a wealth of 'real-world' data has emerged supporting positive clinical, endoscopic, and histological outcomes in patients treated with UST, as well as reassuring safety data. More recently, the results of the first head-to-head trials of UST and tumor necrosis factor (TNF) antagonists were reported. Moreover, a number of studies exploring the role of UST in specific clinical settings, such as perianal CD, postoperative complications and recurrence, extraintestinal manifestations, chronic antibiotic-refractory pouchitis, and pregnancy, were reported. This review explores the results reported to date on UST, including those from pivotal trials, real-world data, and emerging studies regarding therapeutic drug monitoring and immunogenicity. The safety profile of UST was also reviewed.

Upper Gastrointestinal Endoscopy Quality in Italy: A Nationwide Study.

BACKGROUND AND AIMS: International guidelines advise improving esophagogastroduodenoscopy (EGD) quality in Western countries, where gastric cancer is still diagnosed in advanced stages. This nationwide study investigated some indicators for the quality of EGD performed in endoscopic centers in Italy. METHODS: Clinical, endoscopic, and procedural data of consecutive EGDs performed in one month in the participating centers were reviewed and collected in a specific database. Some quality indicators before and during endoscopic procedures were evaluated. RESULTS: A total of 3,219 EGDs performed by 172 endoscopists in 28 centers were reviewed. Data found that some relevant information (family history for GI cancer, smoking habit, use of proton pump inhibitors) were not collected before endoscopy in 58.5-80.7% of patients. Pre-endoscopic preparation for gastric cleaning was routinely performed in only 2 (7.1%) centers. Regarding the procedure, sedation was not performed in 17.6% of patients, and virtual chromoendoscopy was frequently (>75%) used in only one (3.6%) center. An adequate sampling of the gastric mucosa (i.e., antral and gastric body specimens) was heterogeneously performed, and it was routinely performed only by 23% of endoscopists, and in 14.3% centers. CONCLUSIONS: Our analysis showed that the quality of EGD performed in clinical practice in Italy deserves to be urgently improved in different aspects.

Misinterpreting Diarrhea-Predominant Irritable Bowel Syndrome and Functional Diarrhea: Pathophysiological Highlights.

Irritable bowel syndrome with predominant diarrhea (IBS-D) and functional diarrhea (FD) are disorders of gut-brain interaction characterized by recurring symptoms which have a serious impact on the patient's quality of life. Their pathophysiology is far from being completely understood. In IBS-D growing evidence suggests that bile acid malabsorption (BAM) could be present in up to 30% of patients. Microscopic colitis (MC) is a well-known cause of watery diarrhea and some patients, at first, can be diagnosed as IBS-D or FD. Both BAM and MC are often responsible for the lack of response to conventional treatments in patients labelled as "refractory". Moreover, because BAM and MC are not mutually exclusive, and can be found in the same patient, they should always be considered in the diagnostic workout when a specific treatment for BAM or MC is unsatisfactory. In the present review the possible shared pathogenetic mechanisms between BAM and MC are discussed highlighting how MC can induce a secondary BAM. Moreover, a brief overview of the current literature regarding the prevalence of their association is provided.

New Perspectives on Lactose Malabsorption, Celiac Disease and Related Disorders.

Lactose malabsorption (LM) is caused by the incomplete hydrolysis of lactose due to lactase deficiency [...].

Use of tofacitinib as first or second-line therapy is associated with better outcomes in patients with ulcerative colitis: data from a real-world study.

BACKGROUND: Data regarding the real-world (RW) use of tofacitinib (TOF) in patients with ulcerative colitis (UC) are limited. We aimed to investigate TOF's RW efficacy and safety in Italian UC patients. RESEARCH DESIGN AND METHODS: A retrospective assessment of clinical and endoscopic activity was performed according to the Mayo score. The primary endpoints were to evaluate the effectiveness and safety of TOF. RESULTS: We enrolled 166 patients with a median follow-up of 24 (IQR 8-36) weeks. Clinical remission was achieved in 61/166 (36.7%) and 75/166 (45.2%) patients at 8-week and 24-week follow-ups, respectively. The optimization was requested in 27 (16.3%) patients. Clinical remission was achieved more frequently when TOF was used as a first/second line rather than a third/fourth line treatment (p = 0.007). Mucosal healing was reported in 46% of patients at the median follow-up time. Colectomy occurred in 8 (4.8%) patients. Adverse events occurred in 12 (5.4%) patients and severe in 3 (1.8%). One case of simple Herpes Zoster and one of renal vein thrombosis were recorded. CONCLUSIONS: Our RW data confirm that TOF is effective and safe in UC patients. It performs remarkably better when used as the first/second line of treatment.

Real-world efficacy and safety of vedolizumab in managing ulcerative colitis versus Crohn's disease: results from an Italian multicenter study.

BACKGROUND: Vedolizumab (VDZ) can be used to treat refractory ulcerative colitis (UC) and Crohn's disease (CD). We assessed whether there are differences in treating UC vs CD with VDZ. RESEARCH DESIGN AND METHODS: Mayo score in UC and the Harvey-Bradshaw Index (HBI) in CD scored the clinical activity. Achievement and maintenance of clinical remission during the follow-up, and safety were the primary endpoints. RESULTS: 729 patients (475 with UC and 254 with CD), median follow-up of 18 (IQR 6-36) months, were enrolled. Clinical remission at the 6th month of treatment was achieved in 488 (66.9%) patients (74.4% in CD vs 62.9% in UC, p<0.002) while, during the follow-up, no difference was found (81.5% in the UC group and 81.5% pts in the CD group; p=0.537). The clinical remission at the 6th month of treatment (p=0.001) and being naïve to biologics (p<0.0001) were significantly associated with prolonged clinical remission. The clinical response was significantly higher in UC (90.1%) vs CD (84.3%) (p=0.023), and surgery occurred more frequently in CD (1.9% in UC vs 5.1% in CD, p=0.016). CONCLUSION: We found differences when using VDZ in UC vs CD in real life. These parameters can help the physician predict this drug's longterm efficacy.

Pharmacotherapeutic advances for chronic idiopathic constipation in adults.

INTRODUCTION: Chronic idiopathic constipation is a common gastrointestinal disorder whose treatment is still far from being satisfactory for patients. Osmotic laxatives, in particular polyethylene glycol, are the first-line approach, but new emerging pharmacological agents may be useful in refractory patients. AREAS COVERED: Published articles regarding the development and clinical efficacy of new agents in treating chronic idiopathic constipation were reviewed. Among emerging agents, elobixibat, a drug blocking the reabsorption of bile acids, is a promising one, especially in slow transit constipation. Linaclotide, lubiprostone and plecanatide, by a secretagogue action, improve stool consistency and increase colonic transit. Apart from prucalopride, approved in Europe for refractory chronic idiopathic constipation patients, the selective 5-HT4 agonists velusetrag and naronapride are in advanced development. In addition, relamorelin, a ghrelin agonist, seems promising for accelerating colonic transit. EXPERT OPINION: Several new promising drugs have been released with the potential to be effective in the treatment of chronic idiopathic constipation. On the other hand, the experience with these new agents is still limited, especially for long-term treatment. Another important point is that these new treatments for chronic idiopathic constipation are not available worldwide and their use could be somewhat limited by their still relatively high cost.

Translational Gap between Guidelines and Clinical Medicine: The Viewpoint of Italian General Practitioners in the Management of IBS.

Irritable bowel syndrome (IBS) guidelines are generally developed by experts, with the possibility of a translational gap in clinical medicine. The aim of our study was to assess an Italian group of general practitioners (GPs) for their awareness and use of criteria for the diagnosis and management of IBS. For this purpose, a survey was carried out involving 235 GPs, divided into two groups according to their years of activity: 65 "junior general practitioners" (JGPs) (≤10 years) and 170 "senior general practitioners" (SGPs) (>10 years). JGPs were more familiar with the Rome IV Criteria and Bristol Scale than SGPs. Abdominal pain, bowel movement frequency and bloating were the symptoms most frequently used to make a diagnosis. The most probable causes of IBS were reported to be abnormal gastrointestinal motility and psychological triggers. SGPs reported more frequently than JGPs that challenging management and patient's request were motivations for a gastroenterological consultation. The practice of clinical medicine is still far from the guidelines provided by the specialists. Abdominal pain related to defecation and changes in bowel frequency are considered to be the more important symptoms for IBS diagnosis, but most GPs, both JGPs and SGPs, like to consider abdominal bloating as another useful symptom. Involving both gastroenterologists and GPs in developing shared guidelines would be highly desirable in order to improve IBS management strategies in everyday clinical practice.

Lactose Malabsorption and Presumed Related Disorders: A Review of Current Evidence.

BACKGROUND: Lactose malabsorption (LM) is a frequent clinical problem associated with several digestive and extra-digestive diseases. The aim of this manuscript was to clarify the real clinical impact of LM on these disorders. METHODS: A literature search for digestive and extra-digestive disorders related to LM was carried out using PubMed, Medline and Cochrane. RESULTS: A transient lactase deficiency is present in celiac disease (CD) on a normal diet. The persistence of symptoms in CD on a gluten-free diet may be instead, in part, attributed to a primary LM. Similar circumstances are present in inflammatory bowel diseases (IBD), in which LM can be responsible for a part of persistent symptoms in IBD on clinical remission. LM and irritable bowel syndrome (IBS) are instead independent conditions. On the other hand, a lactose-restricted diet may be useful for some IBS patients. A reduced lactose intake can lead to low bone mass and limited risk of fragility fractures. Finally, the absorption of levothyroxine could be conditioned by LM. CONCLUSIONS: LM can be responsible for persistent symptoms in CD and IBD. The association with IBS seems to be casual. Bone mass and levothyroxine absorption can be affected by LM.

Effects of Prokinetics on the Digestive Tract.

BACKGROUND: Functional gastrointestinal disorders account for at least a third of visits to gastroenterology clinics. Despite pathophysiological complexity, impaired gut motility may be frequently present in these disorders. INTRODUCTION: Prokinetics are a class of drugs that promote gastrointestinal motility, accelerate transit, and potentially improve digestive symptoms. Several prokinetic agents with a great variety of mechanisms of action are available. AIM: The purpose of this paper is to update our current knowledge about the efficacy and safety of prokinetics. METHODS: A literature search on efficacy and safety of prokinetics was carried out using the online databases of Pubmed, Medline, and Cochrane. RESULTS: Based on the action of different receptors, prokinetics mainly comprise dopamine antagonists, 5HT4 agonists, motilin agonists, ghrelin agonists, and cholinergic agonists. Prokinetics have the potential to improve motility function in all segments of the digestive tract, from the esophagus to the colon. In particular, drug international agencies have approved antidopaminergic metoclopramide for the treatment of gastroparesis and serotoninergic prucalopride for chronic constipation not responsive to traditional laxatives. Arrhythmias by QT prolongation and galactorrhea by prolactin stimulation are the more frequent side effects related to prokinetics use. CONCLUSION: Old and new prokinetics are effective in ameliorating digestive motility disorders and related symptoms and are widely prescribed. Special attention should be paid to the potential adverse events of these agents.

Chronic Idiopathic Constipation in Adults: A Review on Current Guidelines and Emerging Treatment Options.

Chronic idiopathic constipation (CIC) is a common functional bowel disorder characterized by difficult, infrequent, and/or incomplete defecation. It has a great impact on the quality of life and on health care system and represents a heavy economic burden. The diagnosis is based on symptoms, classified by the Rome IV criteria. The aim of this review was to evaluate the current therapeutic guidelines for adult CIC and highlight new emerging treatments. In detail, European, French, Spanish and Korean guidelines have been identified and compared. Osmotic laxatives, and in particular polyethylene glycol, represent the first-line therapeutic approach. Stimulant laxatives are recommended as a second-line therapy. Pelvic floor rehabilitation is recommended in patients with ano-rectal dyssynergia. In patients who fail to improve with pharmacological therapies sacral nerve stimulation is considered as last chance before surgery. Surgical approach has however limited indications in selected cases. Inertia coli refractory to any approach and obstructed defecation are two subtypes which can benefit from surgery. Among emerging agents, prucalopride, a prokinetic agent, is recommended as a second-line treatment in refractory CIC patients. In addition, the secretagogues linaclotide and plecanatide and the bile acid transported inhibitor elobixibat can be effective in patients not responsive to a second-line therapeutic regimen, although they are not worldwide commercially available.

Hydrogen Breath Tests: Are They Really Useful in the Nutritional Management of Digestive Disease?

BACKGROUND: Carbohydrate malabsorption is a frequent digestive problem associated with abdominal pain, bloating and diarrhea. Hydrogen breath testing (BT) represents the most reliable and validated diagnostic technique. The aim of this manuscript was to clarify the usefulness of BTs in the nutritional management of these disorders. METHODS: A literature search for BT related to carbohydrate malabsorption was carried out using the online databases of Pubmed, Medline and Cochrane. RESULTS: Lactose BT showed good sensitivity and optimal specificity for lactose malabsorption. However, an accurate diagnosis of lactose intolerance should require blind lactose challenge although this method is difficult to utilize in clinical practice. Regarding dose-depending fructose and sorbitol malabsorption, BTs could not add diagnostic advantage compared with a direct dietary intervention. In addition, carbohydrates are fundamental components of fermentable oligo-, di- and monosaccharides and polyols (FODMAPs). Before starting a low FODMAP diet, lactose BT should be suggested in a population with low prevalence of hypolactasia. CONCLUSIONS: BTs represent a valid and noninvasive technique in many digestive conditions. Regarding the management of carbohydrate intolerance, lactose BT can be recommended with some limitations. No sufficient evidence is available about the usefulness of BTs for other sugars in clinical practice.

Safety and protection in endoscopic services during phase II of COVID-19 pandemic: a national survey.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic requires appropriate measures for containing infection spreading. Endoscopic procedures are considered at increased risk of infection transmission. We evaluated organizational aspects and personal behaviours in Italian Endoscopic Units during phase II of the pandemic. METHODS: A questionnaire on organizational aspects and use of personal protective equipment (PPE) were e-mailed to gastroenterologists working in Endoscopic Units. Data were analysed accordingly to the National Health Institute and Gastroenterology Societies recommendations. RESULTS: Data of 117 centres were collected, and different shortcomings emerged. Specific protocols for containing infection and training programs for operators were lacking in 20 and 30% of centres, respectively, and telephone triage 24-72 h before the endoscopy was not implemented in 25% of hospitals. In 30% of centres, the slot time for endoscopies and between examinations was not prolonged. PPE, masks, shirts and gloves were universally adopted, although with some differences. In 20% of centres, a FFPE-FFP3 mask was not adopted during endoscopic examinations. Postendoscopy patient tracking/contact was completed in only one-third of centres. CONCLUSIONS: Our survey provides information on organizational and medical behaviours during COVID-19 phase II in Italy, which could be useful for adopting appropriate measures for containing COVID-19 spread during phase II.

New Perspectives on Gluten-Free Diet.

Celiac disease (CD) is a permanent, chronic, gluten-sensitive disorder characterized by small intestinal inflammation and malabsorption in genetically predisposed individuals [...].

Gastroparesis: New insights into an old disease.

Gastroparesis (Gp) is a chronic disease characterized by a delayed gastric emptying in the absence of mechanical obstruction. Although this condition has been reported in the literature since the mid-1900s, only recently has there been renewed clinical and scientific interest in this disease, which has a potentially great impact on the quality of life. The aim of this review is to explore the pathophysiological, diagnostic and therapeutical aspects of Gp according to the most recent evidence. A comprehensive online search for Gp was carried out using MEDLINE and EMBASE. Gp is the result of neuromuscular abnormalities of the gastric motor function. There is evidence that patients with idiopathic and diabetic Gp may display a reduction in nitrergic inhibitory neurons and in interstitial cells of Cajal and/or telocytes. As regards diagnostic approach, 99-Technetium scintigraphy is currently considered to be the gold standard for Gp. Its limits are a lack of standardization and a mild risk of radiation exposure. The C13 breath testing is a valid and safe alternative method. 13C acid octanoic and the 13C Spirulina platensis recently approved by the Food and Drug Administration are the most commonly used diagnostic kits. The wireless motility capsule is a promising technique, but its use is limited by costs and scarce availability in many countries. Finally, therapeutic strategies are related to the clinical severity of Gp. In mild and moderate Gp, dietary modification and prokinetic agents are generally sufficient. Metoclopramide is the only drug approved by the Food and Drug Administration for Gp. However, other older and new prokinetics and antiemetics can be considered. As a second-line therapy, tricyclic antidepressants and cannabinoids have been proposed. In severe cases the normal nutritional approach can be compromised and artificial nutrition may be needed. In drug-unresponsive Gp patients some alternative strategies (endoscopic, electric stimulation or surgery) are available.

A SIGE-SINGEM-AIGO technical review on the clinical use of esophageal reflux monitoring.

Patients with esophageal symptoms potentially associated with gastroesophageal reflux disease such as heartburn, regurgitation, chest pain, or cough represent one of the most frequent reasons for referral to gastroenterological evaluation. The utility of esophageal reflux monitoring in clinical practice is: (1) to accurately define reflux burden, (2) to segregate patients according to reflux monitoring results as true GERD, reflux hypersensitivity and functional heartburn, and (3) to establish a treatment plan. With this in mind, in the last decade, investigations and technical advances, with the introduction of impedance-pH monitoring and wireless pH capsule, have enhanced our understanding and management of GERD. The following recommendations were discussed and approved after a comprehensive review of the medical literature pertaining to reflux testing techniques and their recent application. This review created under the auspices of the Società Italiana di Gastroenterologia ed Endoscopia Digestiva (SIGE), Società Italiana di Neuro-Gastro-Enterologia e Motilità (SINGEM) and Associazione Italiana Gastroenterologi ed Endoscopisti Digestivi Ospedalieri (AIGO) is intended to help clinicians in applying reflux studies in the most fruitful manner within the context of their patients with esophageal symptoms.

Irritable Bowel Syndrome and Gluten-Related Disorders.

Background: Irritable bowel syndrome (IBS) is frequently associated with celiac disease (CD) and nonceliac gluten/wheat sensitivity (NCGS/NCWS), but epidemiological and pathophysiological aspects are still unclear. Furthermore, a gluten-free diet (GFD) can positively influence IBS symptoms. Methods: A comprehensive online search for IBS related to CD, NCGS and GFD was made using the Pubmed, Medline and Cochrane databases. Results: Although a systematic screening for CD in IBS is not recommended, CD prevalence can be increased in diarrhea-predominant IBS patients. On the other hand, IBS symptoms can be persistent in treated CD patients, and their prevalence tends to decrease on a GFD. IBS symptoms may overlap and be similar to those associated to nonceliac gluten and/or wheat sensitivity. Increased gut permeability could explain the gluten/wheat effects in IBS patients. Finally, a GFD could improve symptoms in a subgroup of IBS patients. Conclusions: The possible interplay between IBS and gluten-related disorders represents a scientifically and clinically challenging issue. Further studies are needed to confirm these data and better clarify the involved pathophysiological mechanisms.

Plecanatide for the treatment of chronic idiopathic constipation in adult patients.

Introduction. Chronic idiopathic constipation (CIC) is a functional gastrointestinal disorder that is associated with an increased healthcare cost and an abnormally poor quality of life. Plecanatide is a natural analog to the peptide agonist of the guanylate cyclase-C (GC-C) receptor, uroguanylin. The conversion of guanosine 5-triphosphate to cyclic guanosine monophosphate results in an increased bowel fluid secretion. Plecanatide is a promising new agent for CIC unresponsive to current therapeutic regimes.Areas covered. A comprehensive online search of Medline and the Science Citation Index was made using the keywords 'plecanatide', 'guanylate cyclase-C agonists', and 'constipation', in various combinations. We reviewed the pharmacodynamics, pharmacokinetics, and metabolism of this agent, and the most significant studies regarding the clinical efficacy and safety of plecanatide in CIC therapy.Expert opinion. Experimental studies showed that plecanatide was significantly better than placebo in reducing CIC severity, straining, stool consistency, bowel movements and quality of life. Apart from limited cases of diarrhea, no serious adverse events were reported. However, few data are available on its long-term safety. Furthermore, patients' affordability of plecanatide can be limited by its costs. Finally, this new agent with a different way of action can be proposed in patients refractory to common therapy.

Prucalopride for the treatment of constipation: a view from 2015 and beyond.

INTRODUCTION: Prucalopride is a prokinetic drug, that has been commercially available in recent years for the treatment of chronically constipated patients. In this update of a previous 2016 article, we reviewed the more recent data supporting its role in the treatment of constipation and constipation-associated conditions. Areas covered: We carried out an extensive literature review on the effects of prucalopride for the years 2012-2018 by means of scientific databases and manual research. More evidence was found on its possible therapeutic role in conditions in which constipation plays a role as an associated symptom, such as opioid-induced constipation, constipation-predominant irritable bowel syndrome, post-operative ileus, colonic diverticular disease, drug-related constipation, and chronic intestinal pseudo-obstruction. Expert opinion: Based on the added literature evidence, we feel that prucalopride is an effective, although expensive, drug for the treatment of primary and secondary forms of constipation, and of other clinical conditions associated with constipation.