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Background: Vedolizumab (VDZ) and infliximab are used to treat moderate to severe ulcerative colitis (UC). The choice of the drug to use at first-line is often based on a combination of clinical and economic factors. The cost of treatment pathway is rarely considered. Therefore, this cost-consequence analysis (CCA) investigated the overall costs of treatment pathway for vedolizumab followed by infliximab (VDZ → IFX) compared to infliximab followed by vedolizumab (IFX → VDZ). Methods: We used a published cost-consequence model (CCM), based on a targeted literature search reporting the time-on-treatment data for vedolizumab or infliximab in UC in first and second-line of treatment. CCM time horizon was defined by the length of treatment sequences. Considering the Italian hospital perspective, the CCA evaluated the biologic drugs acquisition costs, drug administration costs, hospitalization costs, switch costs, colectomy costs and third-line treatment costs. Third-line options included colectomy, tofacitinib, ustekinumab or dose escalation of second-line biologic. Results: Over the 5.2-year time horizon (duration of the longer VDZ → IFX pathway), the mean cost per patient of VDZ → IFX pathway was slightly lower than the mean cost per patient of IFX → VDZ pathway (€ 86,339 vs 89,636). The CCM predicted that using VDZ as first-line treatment delayed the time to costly third-line therapies compared to first-line using IFX (VDZ-first-line median time-on-treatment 3.6-years and IFX-second-line 1.6-years; IFX-first-line 1.4-years and VDZ-second-line 2.3-years and third-line 1.5-years). Conclusion: The CCA showed that a biologic treatment pathway that begins with first-line vedolizumab is not more expensive than one beginning with first-line infliximab and delayed the time to costly third-line.

A 80-year-old woman underwent vulvar melanoma resection and segmental lung resection for pulmonary metastasis. Immunotherapy with Nivolumab was performed. One year later, the patient was admitted for gastrointestinal (GI) recurrent bleeding and severe anemia. Esophagoastroduodenoscopy and colonoscopy did not show any abnormality, while videocapsule endoscopy (VCE) revealed an irregular and exophytic whitish area with a “coal-black” central depression. Small bowel resection was performed and histological examination revealed S100 protein strongly positive melanoma metastasis. The patient died six months later from disease progression. A “coal-black” appearance of intestinal metastatic melanoma has been described only twice before this report. In one case the patient had been treated by immunotherapy with interferon A and dendritic cell-based vaccination. In our patient, it is presumable that the picture we observed was a consequence of Nivolumab treatment inducing the disappearance of melanocytes in the area surrounding the metastasis with the onset of the central coal-black lesion encircled by whitish tissue. This picture should be emblematic of intestinal metastatic melanoma in subjects treated with immunotherapy showing occult/obscure bleeding.

Background. The lifelong and remitting nature of ulcerative colitis results in considerable disability and a substantial negative impact on quality of life. The major goal of the therapy of ulcerative colitis is considered to be the modification of the course of the disease, so that the patient’s quality of life can be improved while minimising disease-related disability. Although considerable progress in understanding the molecular pathways involved in ulcerative colitis has led to improved treatment options, there is currently no definitive cure for ulcerative colitis, there remain considerable unmet needs in terms of long-term efficacy and safety, and there are many patients who continue to be burdened by physical and psychological symptoms. Defining unmet needs can help to increase the awareness of the shortcomings of current therapeutic management and highlight the need to achieve not only a control of clinical symptoms but also control of mucosal healing, in order to attain the best possible long-term outcomes. Methods. With the aim of providing a better understanding of the unmet needs of patients towards improving overall care, a Delphi process was used to obtain consensus among a group of Italian ulcerative colitis experts. The consensus group met with a major focus of delineating the unmet needs of current treatment strategies and overall management of ulcerative colitis, while also focusing on quality of life and patient care. Results. Three main areas were identified: (i) treatment, (ii) monitoring and risk management, and (iii) patient-related issues. A high level of consensus was reached on all but one of the statements identified. Conclusions. The findings arising from the Delphi process provide valuable insights into the unmet needs in the management of moderate-to-severe ulcerative colitis from the clinician’s perspective, while emphasising the benefits of therapeutic individualization and suggesting areas that need additional study with the aim of optimising the treatment of patients with ulcerative colitis.

Concomitant inflammatory bowel disease (IBD) and hepatitis C virus (HCV) infection is a relevant comorbidity since IBD itself exposes to a high risk of liver damage. We aimed to evaluate liver stiffness (LS) in IBD-HCV after antiviral treatment. We enrolled IBD patients with HCV. All patients at baseline underwent LS measurement by elastography. Patients who were eligible for antiviral therapy received direct antiviral agents (DAAs) and sustained viral response was evaluated at the 12th week. A control group was selected within IBD patients without HCV. One year later, all IBD-HCV patients and controls repeated LS measurement. Twenty-four IBD-HCV patients and 24 IBD controls entered the study. Only twelve out of 24 received DAAs and all achieved sustained viral response (SVR). All IBD subjects were in remission at enrollment and maintained remission for one year. After one year, IBD patients who eradicated HCV passed from a liver stiffness of 8.5 ± 6.2 kPa to 7.1 ± 3.9, p = 0.13. IBD patients who did not eradicate HCV worsened liver stiffness: from 7.6 ± 4.4 to 8.6 ± 4.6, p = 0.01. In the IBD control group, stiffness decreased from 7.8 ± 4.4 to 6.0 ± 3.1, p < 0.001. In conclusion, HCV eradication is able to stop the evolution of liver fibrosis in IBD, while failure to treat may lead to its progression. A stable IBD remission may improve LS even in non-infected subjects.

Antibiotic resistance has become an emerging problem for treating Helicobacter pylori (H. pylori) infection. Clarithromycin and levofloxacin are two key antibiotics used for its eradication. Therefore, we reviewed our experience with genotypic resistance analysis in stools to both clarithromycin and levofloxacin in the last four years to evaluate time trends, both in naive and failure patients. Patients collected a fecal sample using the THD fecal test device. Real-time polymerase chain reaction was performed to detect point mutations conferring resistance to clarithromycin (A2142C, A2142G, and A2143G in 23S rRNA) and levofloxacin (substitutions at amino acid position 87 and 91 of gyrA). One hundred and thirty-five naive patients were recruited between 2017–2020. Clarithromycin resistance was detected in 37 (27.4%). The time trend did not show any significant variation from 2017 to 2020 (p = 0.33). Primary levofloxacin resistance was found in 26 subjects (19.2%), and we observed a dramatic increase in rates from 2017 (10%) to 2018 (3.3%), 2019 (20%), and 2020 (37.8%). Ninety-one patients with at least one eradication failure were recruited. Secondary resistance to clarithromycin and levofloxacin was found in 59 (64.8%) and 45 patients (59.3%), respectively. In conclusion, our geographic area has a high risk of resistance to clarithromycin. There is also a progressive spreading of levofloxacin-resistant strains.

We performed an epidemiologic study to assess the prevalence of chronic viral hepatitis in inflammatory bowel disease (IBD) and to detect their possible relationships. Methods: It was a single centre cohort cross-sectional study, during October 2016 and October 2017. Consecutive IBD adult patients and a control group of non-IBD subjects were recruited. All patients underwent laboratory investigations to detect chronic hepatitis B (HBV) and C (HCV) infection. Parameters of liver function, elastography and IBD features were collected. Univariate analysis was performed by Student’s t or chi-square test. Multivariate analysis was performed by binomial logistic regression and odds ratios (ORs) were calculated. We enrolled 807 IBD patients and 189 controls. Thirty-five (4.3%) had chronic viral hepatitis: 28 HCV (3.4%, versus 5.3% in controls, p = 0.24) and 7 HBV (0.9% versus 0.5% in controls, p = 0.64). More men were observed in the IBD–hepatitis group (71.2% versus 58.2%, p < 0.001). Patients with IBD and chronic viral hepatitis had a higher mean age and showed a higher frequency of diabetes, hypertension and wider waist circumference. They suffered more frequently from ulcerative colitis. Liver stiffness was greater in subjects with IBD and chronic viral hepatitis (7.0 ± 4.4 versus 5.0 ± 1.2 KPa; p < 0.001). At multivariate analysis, only old age directly correlated with viral hepatitis risk (OR = 1.05, 95%CI 1.02–1.08, p < 0.001). In conclusion, the prevalence of HBV/HCV in IBD is low in our region. Age may be the only independent factor of viral hepatitis–IBD association. Finally, this study firstly measured liver stiffness in a large scale, showing higher values in subjects with both diseases.

Helicobacter pylori (H. pylori) may enter a non-replicative, non-culturable, low metabolically active state, the so-called coccoid form, to survive in extreme environmental conditions. Since coccoid forms are not susceptible to antibiotics, they could represent a cause of therapy failure even in the absence of antibiotic resistance, i.e., relapse within one year. Furthermore, coccoid forms may colonize and infect the gastric mucosa in animal models and induce specific antibodies in animals and humans. Their detection is hard, since they are not culturable. Techniques, such as electron microscopy, polymerase chain reaction, loop-mediated isothermal amplification, flow cytometry and metagenomics, are promising even if current evidence is limited. Among the options for the treatment, some strategies have been suggested, such as a very high proton pump inhibitor dose, high-dose dual therapy, N-acetycysteine, linolenic acid and vonoprazan. These clinical, diagnostic and therapeutic uncertainties will represent fascinating challenges in the future.

Ulcerative colitis (UC) endoscopic scores translate mucosal damage into values standardizing image analysis. Due to potential limits of current endoscopic activity indexes, we have elaborated on a new score, the “Extended Mayo Endoscopic Score (EMES),” and evaluated its inter-observer agreement in a multicenter endoscopy team, comparing concordance with the Mayo subscore. Sixteen UC consecutive patients underwent follow-up colonoscopy. Recorded videos were anonymously loaded on a web platform. Thirteen expert endoscopists evaluated UC activity using both Mayo and EMES. EMES was described in every colon segment: erythema (0: absent, 1: mild, 2: moderate, 3: severe), vascular pattern (0: normal, 1: reduction, 2: disappearance), erosions and ulcers (0: absent, 1: from 1 to 5, 2: 6 to 10, 3: >10). Weighted Fleiss’ kappa with 95% confidence interval (CI) and p-value defined inter-rater agreement. Global inter-observer agreement of EMES was moderate (kappa = 0.56, 95% CI = 0.46–0.67, p < 0.001). The evaluation of each colonic segment showed moderate agreement for all segments: ascending (kappa = 0.46, 95% CI = 0.32–0.60, p < 0.001), transverse (kappa = 0.48, 95% CI = 0.29–0.67, p < 0.001); descending (kappa = 0.49, 95% CI = 0.35–0.64, p < 0.001), sigmoid (kappa = 0.52, 95% CI = 0.39–0.65, p < 0.001) and rectum (kappa = 0.55, 95% CI = 0.42–0.69, p < 0.001). Mayo subscore agreement was similar to global EMES (kappa = 0.53, 95% CI = 0.39–0.66, p = 0.001). Therefore, our report emphasizes the importance of assessing inter-observer agreement for EMES, but also for other known scoring systems, including the Mayo subscore.

Background. Diverticular disease treatment is limited to fibres, antibiotics, and surgery. There is conflicting evidence on mesalazine benefits and harms. Aim. We systematically reviewed current evidence on benefits and harms of mesalazine versus all other treatments in people with diverticular disease. Methods. We searched MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov for studies published to July 2018. We estimated risk ratios (RR) for dichotomous outcomes (disease remission/recurrence, acute diverticulitis in symptomatic uncomplicated diverticular disease, need for surgery/hospitalization, all-cause/disease-related mortality, adverse events), mean differences (MD) or standardized MD (SMD) for continuous outcomes (quality of life, symptoms score, time to recurrence/remission), and their 95% confidence intervals (CI) using random-effects models. We quantified heterogeneity by Chi2 and I2 tests. We performed subgroup analyses by disease subtype, comparator, follow-up duration, mesalazine dose, and mode of administration. Results. We identified 13 randomized trials (n=3028 participants). There was a higher likelihood of disease remission with mesalazine than controls in acute uncomplicated diverticulitis (1 trial, 81 participants, RR=2.67, 95%CI=1.05-6.79), but not in symptomatic uncomplicated diverticular disease (1 trial, 123 participants, RR=1.04, 95%CI=0.81-1.34). There was a lower likelihood of disease recurrence with mesalazine than controls in symptomatic uncomplicated diverticular disease (2 trials, 216 participants, RR=0.52, 95%CI=0.28-0.97), but not in acute uncomplicated diverticulitis (7 trials, 2196 participants, RR=0.90, 95%CI=0.61-1.33). There was no difference in the likelihood of developing acute diverticulitis in symptomatic uncomplicated diverticular disease between the two groups (3 trials, 484 participants, RR=0.26, 95%CI=0.06-1.20). There was a higher global symptoms score reduction with mesalazine than controls in symptomatic uncomplicated diverticular disease (2 trials, 326 participants, SMD=-1.01, 95%CI=-1.51,-0.52) and acute uncomplicated diverticulitis (2 trials, 153 participants, SMD=-0.56, 95%CI=-0.88,-0.24). Conclusions. Mesalazine may reduce recurrences in symptomatic uncomplicated diverticular disease. There is uncertainty on the effect of mesalazine in achieving diverticular disease remission. Mesalazine may not prevent acute diverticulitis in symptomatic uncomplicated diverticular disease.

Background/Aim: In celiac disease (CD), there is increased mRNA coding for tissue transglutaminase (tTG) and interferon gamma (IFNα). In seronegative celiac patients, the mucosal immune complexes anti-tTG IgA/tTG are found. We assayed tTG- and IFNα-mRNA in the mucosa of patients with a clinical suspicion of seronegative CD and correlated the values with intraepithelial CD3 lymphocytes (IELs). Materials and Methods: Distal duodenum specimens from 67 patients were retrieved and re-evaluated for immunohistochemically proven CD3 IELs. Five 10 μm sections were used for the extraction and assay of tTG and IFNα coding mRNA levels using reverse transcriptase real-time polymerase chain reaction (RT-PCR). Samples from 15 seropositive CD patients and 15 healthy subjects were used as positive and negative controls. Results were expressed as fold-change. Results: Our series was divided into three groups based on IEL count: >25 (14 patients: group A), 15–25 (26 patients: group B), and 0–15 (27 patients: Group C). tTG-mRNA levels were (mean ± SD): CD = 9.8 ± 2.6; group A = 10.04 ± 4.7; group B = 4.99 ± 2.3; group C = 2.26 ± 0.8, controls = 1.04 ± 0.2 (CD = group A > group B > group C = controls). IFNα-mRNA levels were: CD = 13.4 ± 3.6; group A = 7.28 ± 3.6; group B = 4.45 ± 2.9; group C = 2.06 ± 1.21, controls = 1.04 ± 0.4. Conclusions: Our results suggest that tTG- and IFNγmRNA levels are increased in both seropositive and potential seronegative patients with CD, showing a strong correlation with the CD3 IEL count at stage Marsh 1. An increase in both molecules is found even when IELs are in the range 15–25 (Marsh 0), suggesting the possibility of a "gray zone" inhabited by patients which should be closely followed up in gluten-related disorders.

Background and Aims. Nonceliac gluten sensitivity (NCGS) is a gluten-related emerging condition. Since few data about NCGS histopathology is available, we assessed the markers of lymphocyte and innate immunity activation. Materials and Methods. We retrieved duodenal biopsy samples of patients with NCGS diagnosis according to the Salerno criteria. We selected specimens of positive (seropositive celiac disease/Marsh 1-2 stage) and negative (normal microscopic picture) controls. Immunohistochemistry for CD3 (intraepithelial lymphocytes-IELs), CD4 (T helper lymphocytes), CD8 (T cytotoxic lymphocytes), and CD1a/CD117 (Langerhans/mast cells) was performed. ANOVA plus Bonferroni’s tests were used for statistical analysis. Results. Twenty NCGS, 16 celiac disease, and 16 negative controls were selected. CD3 in NCGS were higher than negative controls and lower than celiac disease (18.5 ± 6.4, 11.9 ± 2.8, and 40.8 ± 8.1 IELs/100 enterocytes; p

Background and objectives: Video-capsule endoscopy (VCE) has shown a large range (38⁻83%) of diagnostic yield in unexplained iron deficiency anemia (IDA) and obscure-occult bleeding. Therefore, we retrospectively investigated the VCE-detected spectrum and the prevalence of small bowel injuries and associated risk factors in inpatients with both of the above reported conditions. Methods: We selected inpatients with IDA (hemoglobin t-test and Fisher’s exact test for continuous and categorical variables, respectively, in univariate analysis. For multivariate analysis, we used binomial logistic regression. Results: We retrieved 109 patients (female:male ratio of 53:56; age 63.4 ± 18.9 years). Eighty patients (73.4%) showed ≥1 small bowel lesions. The Lewis score was calculated in 41 patients: 13 (31.7%) showed a mild (790, respectively) score. In univariate analysis, the small bowel transit time (6.2 ± 2.9 versus 5.2 ± 2.1 h; p = 0.049) and non-steroidal anti-inflammatory drug use for at least two weeks (17.5% versus 0%; p = 0.01) were significantly higher in subjects with injuries. These associations were not confirmed at multivariate analysis. The severity of a lesion directly correlated with proton pump inhibitor (PPI) use and duration (not confirmed in multivariate analysis). VCE can reveal the source of obscure-occult bleeding in a high percentage of unexplained IDAs. A wide spectrum of endoscopic pictures may be found. Known as well as supposed risk factors for small bowel lesions may be detected.

Objectives. To retrospectively compare the results of the MRIA (magnetic resonance index of activity) with a modified MRIA (mMRIA), which was calculated excluding from MRIA formula the data of relative contrast enhancement (RCE). Materials and Methods. MR-E and corresponding endoscopic records of 100 patients were reviewed. MRIA, mMRIA, and SES endoscopic index were calculated for all the patients. Namely, MRIA was calculated as follows: (1.5 × wall thickening + 0.02 × RCE + 5 × intramural edema + 10 × ulcers), while mMRIA was calculated with the modified formula (1.5 × wall thickening + 5 × intramural edema + 10 × ulcers). Results. Mean MRIA and mMRIA values were 19.3 and 17.68, respectively p

Cirrhosis has always been regarded as hemorrhagic coagulopathy caused by the reduction in the hepatic synthesis of procoagulant proteins. However, with the progression of liver disease, the cirrhotic patient undergoes a high rate of thrombotic phenomena in the portal venous system. Although the progression of liver failure produces a reduction in the synthesis of anticoagulant molecules, a test able to detect the patients with hemostatic balance shifting towards hypercoagulability has not yet been elaborated. The need of treatment and/or prophylaxis of cirrhotic patients is demonstrated by the increased mortality, the risk of bleeding from esophageal varices, and the mortality of liver transplantation, when portal vein thrombosis (PVT) occurs even if current guidelines do not give indications about PVT treatment in cirrhosis. In view of the general feeling that the majority of cirrhotic patients at an advanced stage may be in a procoagulant condition (suggested by the sharp increase in the prevalence of PVT), it is presumable that a prophylaxis of this population could be of benefit. The safety and the efficacy of prophylaxis and treatment with enoxaparin in patients with cirrhosis demonstrated by a single paper suggest this option only in controlled trials and, currently, there are no sufficient evidences for a recommendation in the clinical practice.