Empirical rescue treatment of Helicobacter pylori infection in third and subsequent lines: 8-year experience in 2144 patients from the European Registry on H. pylori management (Hp-EuReg).

OBJECTIVE: To evaluate the use, effectiveness and safety of Helicobacter pylori empirical rescue therapy in third and subsequent treatment lines in Europe. DESIGN: International, prospective, non-interventional registry of the clinical practice of European gastroenterologists. Data were collected and quality reviewed until October 2021 at Asociación Española de Gastroenterología-Research Electronic Data Capture. All cases with three or more empirical eradication attempts were assessed for effectiveness by modified intention-to-treat and per-protocol analysis. RESULTS: Overall, 2144 treatments were included: 1519, 439, 145 and 41 cases from third, fourth, fifth and sixth treatment lines, respectively. Sixty different therapies were used; the 15 most frequently prescribed encompassed >90% of cases. Overall effectiveness remained <90% in all therapies. Optimised treatments achieved a higher eradication rate than non-optimised (78% vs 67%, p<0.0001). From 2017 to 2021, only 44% of treatments other than 10-day single-capsule therapy used high proton-pump inhibitor doses and lasted ≥14 days. Quadruple therapy containing metronidazole, tetracycline and bismuth achieved optimal eradication rates only when prescribed as third-line treatment, either as 10-day single-capsule therapy (87%) or as 14-day traditional therapy with tetracycline hydrochloride (95%). Triple amoxicillin-levofloxacin therapy achieved 90% effectiveness in Eastern Europe only or when optimised. The overall incidence of adverse events was 31%. CONCLUSION: Empirical rescue treatment in third and subsequent lines achieved suboptimal effectiveness in most European regions. Only quadruple bismuth-metronidazole-tetracycline (10-day single-capsule or 14-day traditional scheme) and triple amoxicillin-levofloxacin therapies reached acceptable outcomes in some settings. Compliance with empirical therapy optimisation principles is still poor 5 years after clinical practice guidelines update. TRIAL REGISTRATION NUMBER: NCT02328131.

Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid.

BACKGROUND & AIMS: Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with "advanced cirrhosis" because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy. METHODS: Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs). RESULTS: One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42-2.12), INR (1.37, 1.00-1.87), Child-Pugh score (1.79, 1.28-2.50), MELD (1.17, 1.04-1.30) and bilirubin (1.83, 1.11-3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10-3.36), lower albumin levels (0.18, 0.06-0.51), Child-Pugh score (2.43, 1.50-4.04), history of ascites (3.5, 1.85-6.5) and bilirubin (1.30, 1.05-1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA. CONCLUSIONS: An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.

Routes of Stem Cell Administration.

Stem cells are very promising for the treatment of a plethora of human diseases. Numerous clinical studies have been conducted to assess the safety and efficacy of various stem cell types. Factors that ensure successful therapeutic outcomes in patients are cell-based parameters such as source, viability, and number, as well as frequency and timing of intervention and disease stage. Stem cell administration routes should be appropriately chosen as these can affect homing and engraftment of the cells and hence reduce therapeutic effects, or compromise safety, resulting in serious adverse events. In this chapter, we will describe the use of stem cells in organ repair and regeneration, in particular, the liver and the available routes of cell delivery in the clinic for end-stage liver diseases. Factors affecting homing and engraftment of stem cells for each administration route will be discussed.

Adverse Event Profile During the Treatment of Helicobacter pylori: A Real-World Experience of 22,000 Patients From the European Registry on H. pylori Management (Hp-EuReg).

INTRODUCTION: The safety of Helicobacter pylori eradication treatments and to what extent adverse events (AEs) influence therapeutic compliance in clinical practice are hardly known. Our aim was to assess the frequency, type, intensity, and duration of AEs, and their impact on compliance, for the most frequently used treatments in the "European Registry on Helicobacter pylori management." METHODS: Systematic prospective noninterventional registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H. pylori infection in routine clinical practice. All prescribed eradication treatments and their corresponding safety profile were recorded. AEs were classified depending on the intensity of symptoms as mild/moderate/severe and as serious AEs. All data were subject to quality control. RESULTS: The different treatments prescribed to 22,492 patients caused at least 1 AE in 23% of the cases; the classic bismuth-based quadruple therapy was the worst tolerated (37% of AEs). Taste disturbance (7%), diarrhea (7%), nausea (6%), and abdominal pain (3%) were the most frequent AEs. The majority of AEs were mild (57%), 6% were severe, and only 0.08% were serious, with an average duration of 7 days. The treatment compliance rate was 97%. Only 1.3% of the patients discontinued treatment due to AEs. Longer treatment durations were significantly associated with a higher incidence of AEs in standard triple, concomitant, bismuth quadruple, and levofloxacin triple or quadruple therapies. DISCUSSION: Helicobacter pylori eradication treatment frequently induces AEs, although they are usually mild and of limited duration. Their appearance does not interfere significantly with treatment compliance.

Long-term follow-up of diabetic and non-diabetic patients with chronic hepatitis C successfully treated with direct-acting antiviral agents.

BACKGROUND AND AIMS: Clearance of hepatitis C virus (HCV) is associated with improved glycometabolic control in patients with diabetes mellitus (DM) but whether this effect is maintained over the long term with a reduction in liver-related events (LRE) is still debated. To address these issues, we conducted a long-term prospective study on diabetic and non-diabetic patients with chronic hepatitis C cured by direct antiviral agents (DAAs). METHODS: Among 893 recruited patients, 15.7% were diabetic (Group 1) and 84.3% non-diabetic (Group 2); changes in fasting glucose (FG) and glycated haemoglobin (HbA1c) levels were assessed in Group 1 while the incidence of LRE was established in the whole cohort. Differences between groups were evaluated and independent predictors of unfavourable clinical outcome were established. RESULTS: After a mean follow up of 44.5 months, a significant reduction in FG and HbA1c values was found in Group 1. Death was reported in 5.7% of patients in Group 1 vs 1.6% in Group 2 (P = .003), hepatocellular carcinoma (HCC)-free survival was significantly lower in Group 2 (P = .015) as well as LRE-free survival in Group 1 cirrhotic patients (P = .0006). After adjustment for baseline variables, cirrhosis and albumin levels emerged as independent predictors of LRE; low albumin levels, DM and central obesity were associated with HCC risk in cirrhotic patients while insulin therapy emerged as unfavourable predictor among diabetics. CONCLUSIONS: SVR achieved by DAAs is associated with long-term improvement of glycometabolic control in diabetic patients, but among cirrhotics DM still exerts a detrimental effect on the liver.

Review: Extragastric diseases and Helicobacter pylori.

The involvement of Helicobacter pylori infection in many extra-gastroduodenal manifestations remains a fascinating field of investigation. However, for several of these supposed associations, the potential pathogenic mechanism remains unclear. The present review highlights the main associations of H pylori with extra-gastroduodenal manifestations reported during the last year. We searched for the most relevant studies on this topic, published between April 2019 and March 2020, identified using the term "Helicobacter" in the MEDLINE/Pubmed database. Consistent data emerged from studies investigating metabolic syndrome and ischaemic cardiovascular diseases. Other reported fields of investigation were hepatology, especially focused on non-alcoholic steatohepatitis, neurology, including Parkinson's disease and Alzheimer's disease, as well as dermatology. Inflammatory bowel disease (IBD), that comprises Crohn's disease and ulcerative colitis, may originate from a dysregulation of the host's immune response to commensal bacteria in individuals with genetic predisposition. The reduction of biodiversity and other specific imbalances in the faecal microbiome composition of IBD patients compared to that of healthy controls support this hypothesis. In this context, an inverse correlation between H pylori infection and IBD prevalence has been confirmed. Similar results were found in patients with kidney diseases and allergic manifestations. There are indications of the possible involvement of H pylori infection in metabolic syndrome and ischaemic cardiovascular diseases. However, due to a series of factors linked to study designs and the multifactorial pathogenesis of some diseases, further studies are needed.

Vedolizumab for treatment of chronic refractory pouchitis: a systematic review with pool analysis.

BACKGROUND AND OBJECTIVES: about 1%-2% of patients with chronic refractory pouchitis, in the context of ulcerative colitis, end up with a permanent ileostomy. The aim of this systematic review was to collect all published studies involving patients treated with vedolizumab for chronic refractory or antibiotic-dependent pouchitis and then pool the data regarding the effectiveness of this therapeutic strategy. METHODS: a MEDLINE and Web of Science search of all studies published in English until March 17, 2019 was conducted using the terms "vedolizumab and pouchitis". RESULTS: seven studies with a total of 44 patients with chronic pouchitis were included. Twenty-three out of 44 patients (52.3%) had undergone previous treatment with anti-tumor necrosis factor (TNF) drugs. At week 12, 33 out of 44 patients (75%) reported clinical improvement. Endoscopic improvement, evaluated within 6 months of the start of vedolizumab therapy, was obtained in 28 out of the 38 patients in whom such data were available (73.7%). CONCLUSIONS: this first systematic review published in the literature on this issue suggests that vedolizumab has significant efficacy in chronic refractory or antibiotic-dependent pouchitis, also in patients who failed to respond to other treatments including those with anti-TNF agents.

Effectiveness and safety of adalimumab biosimilar ABP 501 in Crohn's disease: an observational study.

BACKGROUND AND OBJECTIVE: there are no studies in the literature about the effectiveness of adalimumab biosimilar ABP 501 in Crohn's disease. The aim of this study was to evaluate its effectiveness and safety. METHODS: an observational study was performed in Crohn's disease patients treated with ABP 501, with the classic induction and maintenance regimen and in Crohn's disease patients who were switched from the adalimumab originator to ABP 501. RESULTS: eighty-seven patients were included in the study, of which 25 were naïve to the adalimumab originator and 62 were switched to ABP 501. In adalimumab-naïve patients, clinical response at three months was 60% (15/25) and clinical remission at three months was 56% (14/25). At six months, 95.2% (59/62) of the patients switched to ABP 501 were still in therapy, without a significant increase of clinical activity (Harvey-Bradshaw index from 3.4, 95% CI = 2.4-4.4, to 3.8, 95% CI = 2.7-4.9, p = 0.23) and inflammatory biomarkers (C-reactive protein from 4.2 mg/l, 95% CI = 2.5-5.9 mg/l, to 3.6 mg/l, 95% CI = 2.2-5 mg/l, p = 0.32). There were no unexpected adverse events during the study period. CONCLUSIONS: our results support ABP 501 as an effective and well-tolerated drug, with a good interchangeability with its originator for the treatment of Crohn's disease.

Incidence of Prostate Cancer in Inflammatory Bowel Disease: A Meta-Analysis.

Background and objectives: Inflammatory bowel disease (IBD) is associated with an increased risk of developing colorectal cancer as well as some extra-intestinal tumors, but there are still limited data about the risk of prostate cancer (PC). To analyze if there is an increased risk of PC in patients affected by IBD, we performed a systematic review with meta-analysis. Materials and Methods: A Pubmed search of all studies comparing standardized incidence ratio (SIR) or odds ratio (OR) or relative risks (RR) of PC between IBD and non IBD groups, published until March 2020 was conducted. The study protocol was registered on PROSPERO. Twelve studies, mostly population studies, were included. The quality score of these studies, evaluated by the Newcastle-Ottawa Scale, was 7. The heterogeneity was high among the studies in which ulcerative colitis (UC) was considered separate from Crohn's disease (CD) and in the studies that considered UC and CD together ("IBD-studies"), while it was low in the studies which considered CD separate from UC. Results: The relative risk of developing PC was 1.71 (95% confidence interval [CI] 1.16-2.51, p = 0.007) in IBD, 1.10 (95%CI 0.98-1.25, p = 0.116) in CD, and 1.22 (95%CI 0.98-1.51, p = 0.07) in UC. Conclusions: Patients with IBD appear to have a slightly increased risk of PC compared to the general population.

Adalimumab versus azathioprine to halt the progression of bowel damage in Crohn's disease: application of Lémann Index.

Background: The Lémann Index (LI) was recently developed to evaluate the cumulative bowel damage in patients with Crohn's disease (CD).Aims: To search for a difference between adalimumab and azathioprine to halt the progression of bowel damage in active CD, using the LI.Methods: A single-centre, retrospective study was conducted. Patients with CD were included if they had colonoscopy and magnetic resonance enterography performed within 4 months from the start of adalimumab or azathioprine and repeated after 12 months of therapy. Primary outcome was reached if the increase of LI after 12 months of treatment was <0.3, the drug was not stopped, and the use of systemic steroids was continued for no more than 3 months.Results: Ninety-one patients were enrolled, 31 (34.1%) of them treated with adalimumab and 60 (65.9%) with azathioprine. Sixty-seven percent of patients treated with adalimumab reached the primary outcome compared to 28.3% of patients treated with azathioprine (p = .0006). The LI in the group on adalimumab therapy decreased after 12 months (from 9.9 to 8.8), while in the group on azathioprine therapy it increased (from 7.7 to 8.8).Conclusion: Treatment with adalimumab halts the progression of bowel damage in CD while that with azathioprine does not.

Risk factors of suspected spondyloarthritis among inflammatory bowel disease patients.

Background: Occurring in approximately 20-30% of patients, spondyloarthritis is the most common extraintestinal manifestation in inflammatory bowel disease (IBD).Aims: To look for risk factors of spondyloarthritis among inflammatory bowel disease patients.Methods: We modified the STRIPP questionnaire created for psoriatic patients and we created a rapid questionnaire for rheumatologic investigation in IBD patients (STRII). We submitted the questionnaire to all consecutive patients with a known spondyloarthritis in our centre and to patients with a negative rheumatological diagnosis to find the cut-off value. Finally, we prospectively submitted the STRII questionnaire to all consecutive IBD patients in our centre.Results: A cut-off ≥3 correlated with spondyloarthritis with an AUC = 0.91. The STRII questionnaire was submitted to 1147 IBD patients. Two hundred and forty-four out of 1147 (21.3%) collected a STRII score of ≥3. Female sex (p < .0001) and Crohn's disease (p = .023) were risk factors. Patients with a history of at least 1 immunosuppressant or biologic drug (p = .002 and p < .0001, respectively) had a higher rate of positivity to STRII questionnaire.Conclusion: Among IBD patients, females, Crohn's disease, those with a history of at least 1 immunosuppressive or biological therapy are at increased risk of spondyloarthritis.

Dual biological therapy with anti-TNF, vedolizumab or ustekinumab in inflammatory bowel disease: a systematic review with pool analysis.

Background: Inflammatory bowel diseases patients eligible for biological therapy represent a group with considerable disease burden and biologics only achieve 40% clinical remission rates in responders after 1 year of therapy. Aims: To collect all the published data about patients treated with dual biological therapy with an Anti-TNF, vedolizumab or ustekinumab, for a period of at least 3 months and to pool the data about the effectiveness and safety. Methods: A MEDLINE, and Web of Science search of all studies published in English until 1 January 2019 was conducted. Results: We included 7 studies with a total of 18 patients. Fifteen patients were treated with a combination of an anti-TNF and vedolizumab, 3 patients were treated with vedolizumab and ustekinumab. Fifty-six percent of patients were affected by Crohn's disease and 50% of patients were treated with an immunosuppressant drug or steroid too. A clinical improvement was obtained in 100% of patients, and an endoscopic improvement in 93% of patients. No serious adverse events were reported. Conclusions: The use of dual biological therapy is an attractive therapeutic option and may be an opportunity to better tailor and personalize the therapies for patients. Further studies, as randomized control trials, to provide comparative efficacy and safety endpoints of combination therapies, and to clarify potential advantages of combined biological therapies, are needed.

Apparent diffusion coefficient and enhancement patterns in MR imaging as markers of severe or moderate ileum inflammation in Crohn's disease.

BACKGROUND AND PURPOSE: magnetic resonance enterography has been increasingly used for the diagnosis and follow-up of Crohn's disease (CD). The purpose of the study was to compare the apparent diffusion coefficient (ADC) with wall enhancement for the differentiation of severe, moderate or no inflammation activity in the ileum. METHODS: a prospective, blinded study was conducted of 46 CD patients with a clinical Crohn's disease activity index (CDAI) ≥ 220 and a simple endoscopic score for Crohn's disease (ES-CD) ≥ 7, which yielded 58 inflamed segments with CD. Twenty controls were also included. All segments were characterized by four ADC readings. The two different enhancement patterns observed in inflamed segments, transmural or mucosal, were associated with severely (23) or moderately (35) active CD. RESULTS: the ADC value decreased from 2.79 ± 0.35 x 10-3 mm2/s for normal segments to 1.81 ± 0.39 x 10-3 mm2/s for the moderately inflamed segments and 1.15 ± 0.20 x 10-3 mm2/s for severely inflamed segments (p ≤ 0.0001). ROC curve analysis on the basis of the three ADC distributions showed a very good discrimination capability with an area under the curve of 0.95. Three groups were defined as follows: normal ileum ADC > 2.4 x 10-3 mm2/s, moderate stages of inflammation 1.5 x 10-3 mm2/s < ADC ≤ 2.4 x 10-3 mm2/s and severe stages of ADC ≤ 1.5 x 10-3 mm2/s. CONCLUSIONS: the ADC value reliably discriminates between normal and inflamed ileum and also distinguishes between severe and moderate inflammation.

Correlation between Thiopurine S-Methyltransferase Genotype and Adverse Events in Inflammatory Bowel Disease Patients.

Background and Objectives: In patients with inflammatory bowel diseases (IBD), the use of azathioprine results in adverse events at a rate of 5% to 20%. The aim of the study was to assess a possible correlation between genetic variability of the enzyme thiopurine S-methyltransferase (TPMT) and the development of toxicity to azathioprine. Materials and Methods: A retrospective, single center, blind, case-control study was conducted on 200 IBD patients, of whom 60 cases suspended azathioprine due to toxicity (leukopenia, pancreatitis, hepatitis, and nausea or vomiting), and 140 controls continued treatment with the drug without adverse events. Results: In the entire cohort, only 8 cases of heterozygous mutations of TPMT were observed, corresponding to 4% mutated haplotype rate, much lower than that reported in literature (close to 10%). No homozygous mutation was found. Regarding the TPMT allelic variants, we did not find any statistically significant difference between patients who tolerated azathioprine and those who suffered from adverse events. (OR = 0.77, 95% CI = 0.08-7.72; p = 0.82). Conclusions: According to our study, in IBD patients, the search for TPMT gene mutations before starting treatment with azathioprine is not helpful in predicting the occurrence of adverse events. Importantly, patients with allelic variants should not be denied the therapeutic option of azathioprine, as they may tolerate this drug.

Helicobacter pylori and nonmalignant upper gastrointestinal diseases.

The review of the most important recent publications concerning the relation of Helicobacter pylori with peptic ulcer disease (PUD), noninvestigated and functional dyspepsia, and gastroesophageal reflux disease (GERD) is presented. H. pylori remains the main etiopathogenetic factor in complicated and uncomplicated PUD. Nevertheless, the role of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin is increasing. The novel data did not confirm that PUD caused by NSAIDs and aspirin is less symptomatic. The role of glucocorticoids, immunosuppressants, and antidepressants seems to be of some importance. Although the involvement of H. pylori in functional dyspepsia is controversial, several data support the importance of H. pylori-induced gastritis in the pathogenesis of dyspeptic symptoms. Recent interventional studies have reported that H. pylori eradication improves dyspepsia mainly in areas with a high prevalence of this bacterium. Novel data regarding the relation of gastrointestinal peptides, ghrelin and obestatin, with H. pylori infection are also presented. Intriguing findings support the involvement of the gastric microbiota in the causation of chronic functional dyspepsia. Finally, some data concerning negative, positive, or neutral associations of H. pylori with gastroesophageal reflux disease (GERD) were published. In this context, today there is no evidence indicating that H. pylori eradication could worsen the symptoms or the course of GERD.

The adherence to the therapy in inflammatory bowel disease: beyond the number of the tablets.

OBJECTIVES: The therapy of the inflammatory bowel diseases is quite complex. A partial compliance increases the relapse probability and the health expenditure. The aim of the study is to correctly study the adherence to the therapy in a single centre eliminating the bias of a different relationship of trust with different doctors. MATERIALS AND METHODS: We conducted a blind prospective study on the adherence evaluated for mesalazine. RESULTS: Three hundred and seventy-six patients were included in the final analysis. Of the patients, 57.4% never missed a single dose of mesalazine, 29.3% missed one or two doses, 7.4% missed three to four doses, 5.9% missed more than five doses. A greater adherence among males (p = .015) and, in ulcerative colitis, among the group with a disease duration of <2 years compared to the one with a disease duration between 2 and 5 years (p = .04) were found. In Crohn's diseases, among the patients who had never undergone to surgical interventions, the adherence was 49.6%, compared to 51.9% among patients who underwent to one surgical resection and 78.6% among patients underwent to multiple surgical resections (p = .001). CONCLUSIONS: The factors influencing the adherence to the therapy are only partly related to the prescribed therapy, but also to factors affecting the patient life: to increase the adherence rate it would be necessary not only interventions on the posology but also the psychological support to the patient at the time of the visit.

Performance of protein induced by vitamin K absence or antagonist-II assessed by chemiluminescence enzyme immunoassay for hepatocellular carcinoma detection: a meta-analysis.

OBJECTIVES: In the setting of surveillance for hepatocellular carcinoma (HCC) detection, the use of serum biomarkers in addition to ultrasonography (US) is still a matter of debate. Hence, we performed a meta-analysis to evaluate the diagnostic accuracy of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) alone or in combination for HCC detection in patients at risk of tumor development. MATERIALS AND METHODS: We performed a systematic search in PubMed and Scopus database for original articles published in English from 2011 to 2017, investigating the accuracy of PIVKA-II alone or in combination with AFP (reported as area under the curve [AUC]) for HCC detection among patients at risk of tumor development. Furthermore, we focused on studies in which serum PIVKA-II was assessed by highly sensitive chemiluminescence immunoassay (CLEIA). RESULTS: A total of 11 studies (873 patients with HCC and 1244 patients with advanced liver disease/cirrhosis) were included in the meta-analysis. The weighted summary AUC (sAUC) of PIVKA-II and AFP for the discrimination between patients with HCC and those without was 0.791 (0.746-0.837) and 0.767 (0.732-0.803), respectively. The combination of PIVKA-II + AFP results in a sAUC of 0.859 (0.837-0.882). The performance for HCC detection of PIVKA-II + AFP was significantly superior to each biomarker used alone (ΔsAUC = 0.068, p = .032 and ΔsAUC = 0.092, p < .001, respectively). CONCLUSION: In clinical practice, the use of PIVKA-II + AFP in addition to US examination may improve the effectiveness of surveillance among patients at risk for HCC development.

A question about dyspeptic patients analyzed using psychometric scores.

Orive et al. reported the results of a randomized study that included patients with functional dyspepsia (FD) treated with standard versus standard plus a psychological approach. Reliability (Cronbach's alpha), validity (confirmatory factor analysis [FA]) and responsiveness were analyzed using specific questionnaires.