Comparative Efficacy of Subcutaneous and Intravenous Infliximab and Vedolizumab for Maintenance Treatment of TNF-naive Adult Patients with Inflammatory Bowel Disease: A Systematic Literature Review and Network Meta-analysis.

BACKGROUND: Infliximab and vedolizumab are widely used to treat Crohn's disease (CD) and ulcerative colitis (UC). AIMS: This systematic review and network meta-analysis evaluated comparative efficacy of various regimens for intravenous or subcutaneous infliximab and vedolizumab during maintenance treatment in CD and UC. METHODS: Parallel-group randomized controlled trials (RCTs) were identified by a systematic literature review (CRD42022383401) and included if they evaluated therapeutics of interest for maintenance treatment of adults with moderate-to-severe luminal CD or UC and assessed clinical remission between Weeks 30 and 60. Clinical remission rates in CD or UC and mucosal healing rates in UC were analyzed in a Bayesian network meta-analysis model. Endoscopic outcomes in CD were synthesized by proportional meta-analysis. RESULTS: Overall, 13 RCTs were included in the analyses. All vedolizumab studies randomized induction responders to maintenance treatment; infliximab studies used a treat-through design. Subcutaneous infliximab 120 mg every 2 weeks had the highest odds ratio (OR) [95% credible interval] versus placebo for clinical remission during the maintenance phase (CD: 5.90 [1.90-18.2]; UC: 5.45 [1.94-15.3]), with surface under the cumulative ranking curve (SUCRA) values of 0.91 and 0.82, respectively. For mucosal healing in UC, subcutaneous infliximab 120 mg every 2 weeks showed the highest OR (4.90 [1.63-14.1]), with SUCRA value of 0.73, followed by intravenous vedolizumab 300 mg every 4 weeks (SUCRA value, 0.70). Endoscopic outcomes in CD were better with subcutaneous infliximab 120 mg every 2 weeks than intravenous infliximab 5 mg/kg every 8 weeks. CONCLUSIONS: Subcutaneous infliximab showed a favorable efficacy profile for achieving clinical remission and endoscopic outcomes during maintenance treatment in CD or UC.

Long-term colonisation with donor bacteriophages following successful faecal microbial transplantation.

BACKGROUND: Faecal microbiota transplantation (FMT) is used in the treatment of recurrent Clostridium difficile infection. Its success is typically attributed to the restoration of a diverse microbiota. Viruses (including bacteriophages) are the most numerically dominant and potentially the most diverse members of the microbiota, but their fate following FMT has not been well studied. RESULTS: We studied viral transfer following FMT from 3 donors to 14 patients. Recipient viromes resembled those of their donors for up to 12 months. Tracking individual bacteriophage colonisation revealed that engraftment of individual bacteriophages was dependent on specific donor-recipient pairings. Specifically, multiple recipients from a single donor displayed highly individualised virus colonisation patterns. CONCLUSIONS: The impact of viruses on long-term microbial dynamics is a factor that should be reviewed when considering FMT as a therapeutic option.

The long-term effects of faecal microbiota transplantation for gastrointestinal symptoms and general health in patients with recurrent Clostridium difficile infection.

BACKGROUND: Faecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection. In short-term the treatment has been shown to be safe, however, there are no large, long-term follow-up studies looking into the potential adverse effects. AIM: To analyse the long-term effect of FMT treatment in patients with recurrent C. difficile infection and to compare the outcome to antibiotic treated patients. METHODS: Altogether 84 patients of which 45 received a FMT treatment and 39 served as controls receiving antibiotics for the infection were followed on average for 3.8 years. Their recovery and medical status was evaluated using a retrospective questionnaire, determining their quality of life, gastrointestinal symptoms and new diseases potentially related to the FMT. RESULTS: There was no difference in the incidence of severe diseases (inflammatory bowel disease, cancer, autoimmune disease, allergy, neurological diseases) between the patient groups. In addition, weight gain did not differ between treatment groups. The FMT treated patients reported that their bowel habits improved significantly faster, they had less irregular bowel function and less symptoms of upper GI-tract when compared to the patients treated with antibiotics. Significantly more patients in FMT-group reported that their mental health improved after the treatment. The willingness to receive FMT treatment for potential new C. difficile infection was significantly higher in both treatment groups compared to other treatment options. CONCLUSION: Our study highlights that FMT is a durable, safe and acceptable treatment option for patients with recurrent C. difficile infection also in long term, and it shows potential benefits over antimicrobial treatment.

Consensus report: faecal microbiota transfer - clinical applications and procedures.

BACKGROUND: Faecal microbiota transplantation or transfer (FMT) aims at replacing or reinforcing the gut microbiota of a patient with the microbiota from a healthy donor. Not many controlled or randomised studies have been published evaluating the use of FMT for other diseases than Clostridium difficile infection, making it difficult for clinicians to decide on a suitable indication. AIM: To provide an expert consensus on current clinical indications, applications and methodological aspects of FMT. METHODS: Well-acknowledged experts from various countries in Europe have contributed to this article. After literature review, consensus has been achieved by repetitive circulation of the statements and the full manuscript among all authors with intermittent adaptation to comments (using a modified Delphi process). Levels of evidence and agreement were rated according to the GRADE system. Consensus was defined a priori as agreement by at least 75% of the authors. RESULTS: Key recommendations include the use of FMT in recurrent C. difficile infection characterised by at least two previous standard treatments without persistent cure, as well as its consideration in severe and severe-complicated C. difficile infection as an alternative to total colectomy in case of early failure of antimicrobial therapy. FMT in inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS) and metabolic syndrome should only be performed in research settings. CONCLUSIONS: Faecal microbiota transplantation or transfer is a promising treatment for a variety of diseases in which the intestinal microbiota is disturbed. For indications other than C. difficile infection, more evidence is needed before more concrete recommendations can be made.

Supragastric belch may be related to globus symptom - a prospective clinical study.

BACKGROUND: The etiology of globus is poorly understood. It is controversial, whether gastroesophageal reflux disease (GERD) has a role in globus. To investigate the possible esophageal background of this symptom, we performed transnasal esophagoscopy (TNE), high-resolution manometry (HRM), and 24-h multichannel intraluminal impedance (MII) and pH monitoring on globus patients. METHODS: Thirty consecutive patients were referred to Helsinki University Hospital, Department of Otorhinolaryngology - Head and Neck Surgery for treatment of globus; 24 consecutive patients with difficult reflux symptoms from the Department of Surgery served as controls. We compared the results of the patient groups in endoscopies, HRM, and 24-h MII-pH monitoring. KEY RESULTS: In MII monitoring, globus patients had supragastric belch (6/20, 30% vs 1/24, 4%; p = 0.038) more often than controls. Total reflux time was higher in controls (p = 0.004), and they had more acid reflux events (p = 0.002) in MII, but between groups, the number of non-acid reflux events was similar. In pH monitoring, DeMeester score and total pH <4 time were higher in controls (P < 0.001). In HRM, the upper esophageal sphincter (UES) mean basal and residual pressures did not differ. CONCLUSIONS & INFERENCES: Supragastric belch was more common in globus patients, suggesting the possible role of this condition in globus sensation. However, globus patients in this series had no acid or non-acid GERD or elevated UES pressure.

Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 2.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality. In many countries, there is a lack of comprehensive epidemiological data that are crucial in implementing disease control measures as new treatment options become available. Published literature, unpublished data and expert consensus were used to determine key parameters, including prevalence, viremia, genotype and the number of patients diagnosed and treated. In this study of 15 countries, viremic prevalence ranged from 0.13% in the Netherlands to 2.91% in Russia. The largest viremic populations were in India (8 666 000 cases) and Russia (4 162 000 cases). In most countries, males had a higher rate of infections, likely due to higher rates of injection drug use (IDU). Estimates characterizing the infected population are critical to focus screening and treatment efforts as new therapeutic options become available.

Strategies to manage hepatitis C virus (HCV) infection disease burden - volume 2.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries, and the relative impact of two scenarios was considered: (i) increased treatment efficacy while holding the treated population constant and (ii) increased treatment efficacy and increased annual treated population. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. In most countries, the annual treated population had to increase several fold to achieve the largest reductions in HCV-related morbidity and mortality. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. In most of the studied countries, the majority of patients were born between 1945 and 1985.

The present and future disease burden of hepatitis C virus (HCV) infections with today's treatment paradigm - volume 2.

Morbidity and mortality attributable to chronic hepatitis C virus (HCV) infection are increasing in many countries as the infected population ages. Models were developed for 15 countries to quantify and characterize the viremic population, as well as estimate the number of new infections and HCV related deaths from 2013 to 2030. Expert consensus was used to determine current treatment levels and outcomes in each country. In most countries, viremic prevalence has already peaked. In every country studied, prevalence begins to decline before 2030, when current treatment levels were held constant. In contrast, cases of advanced liver disease and liver related deaths will continue to increase through 2030 in most countries. The current treatment paradigm is inadequate if large reductions in HCV related morbidity and mortality are to be achieved.

Simple faecal preparation and efficacy of frozen inoculum in faecal microbiota transplantation for recurrent Clostridium difficile infection--an observational cohort study.

BACKGROUND: Faecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection (rCDI). The finding of suitable donor, donor screening and preparation of faecal transplants are challenging in clinical work. AIM: To develop a practical protocol for preparing frozen transplants and to compare the efficacy of previously frozen and fresh faeces in treating rCDI. METHODS: Two healthy volunteers acted as universal donors for the frozen faecal preparations, which were prepared by suspending faeces into physiological saline, adding glycerol to a final concentration of 10% and storing at -80 °C. We compared the outcomes of patients with rCDI who had undergone FMT at colonoscopy and received infusion of previously prepared, freeze-stored faeces (n = 23) or fresh faeces from individual (n = 15) or universal donors (n = 11) (total n = 49). Clinical failure was defined as persistent or recurrent symptoms with a positive C. difficile toxin stool test, and a need for new therapy. RESULTS: At 12 weeks post-FMT, symptoms were resolved in 22 of 23 patients receiving previously frozen faeces, and in all 11 or 14 of 15 patients receiving fresh faeces from the universal or individual donors respectively (totally 25 of 26; P = ns, success rate 96%). Mild transient fever appeared for two patients receiving frozen faeces, but no other significant side effects were observed. 42 patients were followed up for a year post-FMT and the success rate was 88% in both fresh and frozen faeces groups. CONCLUSIONS: Preparation of frozen transplants simplifies the practical aspects of faecal microbiota transplantation without loss of efficacy or safety.

Rifaximin in the treatment of recurrent Clostridium difficile infection.

BACKGROUND: Clostridium difficile can cause severe antibiotic-associated colitis. Conventional treatments with metronidazole and vancomycin improve symptoms, but after discontinuation of treatment, C. difficile infection (CDI) recurs in a number of patients. Rifaximin is a rifamycin-based non-systemic antibiotic that has effect against C. difficile. AIM: To assess the effectiveness of rifaximin in recurrent C. difficile infection. METHODS: We retrospectively evaluated the records of 32 patients who were treated with rifaximin for recurrent C. difficile infection. The symptoms were evaluated 12 weeks after the start of treatment and patient records were followed up until 1 year after treatment. RESULTS: The mean age of the patients was 55 years (median 64, range: 19-84 years). Before the initiation of rifaximin therapy, the patients had undergone, on the average, 4.4 (range: 2-12) antimicrobial courses for C. difficile infection. C. difficile strain typing was performed in 27 patients. Eight (30%) patients had a strain with a DNA profile compatible with the BI/NAP1/027 ribotype. Antibiotic susceptibilities were determined of isolates from 22 patients. Most isolates (68%) had very low MIC-values for rifampin (<0.002 µg/mL) and the highest MIC value was 3.0 µg/mL. Isolates with a DNA profile compatible with the BI/NAP1/027 ribotype had, on the average, higher MICs of rifampin. After 12 weeks 17 (53%) patients had no relapse. The MIC value of rifampin seemed to predict the response to rifaximin treatment. CONCLUSIONS: Rifaximin is a safe treatment for C. difficile infection. It has a reasonable effect in C. difficile infection and it can be considered as an optional treatment for recurrent C. difficile infection.

A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans.

AIMS/HYPOTHESIS: It has recently been suggested that the rs738409 G allele in PNPLA3, which encodes adiponutrin, is strongly associated with increased liver fat content in three different ethnic groups. The aims of the present study were as follows: (1) to try to replicate these findings in European individuals with quantitative measures of hepatic fat content; (2) to study whether the polymorphism influences hepatic and adipose tissue insulin sensitivity; and (3) to investigate whether PNPLA3 expression is altered in the human fatty liver. METHODS: We genotyped 291 Finnish individuals in whom liver fat had been measured using proton magnetic resonance spectroscopy. Hepatic PNPLA3 expression was measured in 32 participants. Hepatic and adipose tissue insulin sensitivities were measured using a euglycaemic-hyperinsulinaemic (insulin infusion 0.3 mU kg(-1) min(-1)) clamp technique combined with infusion of [3-(3)H]glucose in 109 participants. RESULTS: The rs738409 G allele in PNPLA3 was associated with increased quantitative measures of liver fat content (p = 0.011) and serum aspartate aminotransferase concentrations (p = 0.002) independently of age, sex and BMI. Fasting serum insulin and hepatic and adipose tissue insulin sensitivity were related to liver fat content independently of genotype status. PNPLA3 mRNA expression in the liver was positively related to obesity (r = 0.62, p < 0.0001) and to liver fat content (r = 0.58, p = 0.025) in participants who were not morbidly obese (BMI < 40 kg/m(2)). CONCLUSIONS/INTERPRETATION: A common variant in PNPLA3 increases the risk of hepatic steatosis in humans.

Colonic involvement in a patient with chronic lymphocytic leukaemia.

Various gastrointestinal infiltrations have been described in patients with chronic lymphocytic leukaemia (CLL). Here, we report a 69-year-old man with CLL and anaemia in whom the macroscopic finding of colonoscopy was normal, but the histological specimens revealed lymphocytic leukemia in ileum and in colon. If a CLL patient has any symptoms suggesting a possible GI manifestation of the haematologic disease or anaemia not explained by bone marrow infiltration or hemolysis, the diagnostic evaluation should include endoscopies with adequate biopsies.

Prevalence and distribution of gastric intestinal metaplasia and its subtypes.

BACKGROUND AND STUDY AIMS: Intestinal metaplasia, especially type III intestinal metaplasia is considered to be a precursor of gastric cancer and because of this it is suggested that these patients should be followed up by gastroscopy. Our aim was to find out the prevalence of intestinal metaplasia and its subtypes, the appearance of intestinal metaplasia in different parts of the stomach, and the correlation of intestinal metaplasia with other histological and endoscopic findings. PATIENTS AND METHODS: A total of 505 consecutive patients, with a mean age+/-S.D. of 54+/-16 years, had two biopsies taken from the antrum, two from the corpus, and, in 272 cases, two from the angulus of the stomach during routine upper gastrointestinal endoscopy. Histological specimens were examined according to the updated Sydney system and the ones with incomplete intestinal metaplasia were further stained for sulphomucin visualisation to divide these into types II and III. RESULTS: The overall prevalence of intestinal metaplasia was 19%. The prevalence of type III intestinal metaplasia was 2.8%, type II intestinal metaplasia was 4.4%, and complete intestinal metaplasia was 11%. Intestinal metaplasia was found most frequently in the antrum and also in the angulus. There was no type III intestinal metaplasia in the corpus. Intestinal metaplasia was found more frequently in patients with atrophic gastritis than in other patients (p < 0.01). The patients with type III intestinal metaplasia were older than the patients without intestinal metaplasia (mean age of 73 versus 51 years). None of the patients with a totally normal appearing stomach in upper gastrointestinal endoscopy had type II or type III intestinal metaplasia. CONCLUSION: The relatively high overall prevalence of intestinal metaplasia was found in patients referred for gastroscopy in a region of low prevalence of Helicobacter pylori infection and low incidence of gastric cancer. Intestinal metaplasia was most often found in the antrum and angulus. Type III intestinal metaplasia was more prevalent in older patients and intestinal metaplasia was more frequently found in patients with atrophic gastritis. Normal appearing endoscopic finding seems to exclude type II and III intestinal metaplasia.

The clinical value of taking routine biopsies from the incisura angularis during gastroscopy.

BACKGROUND AND STUDY AIMS: The incisura angularis is considered to be a typical site for Helicobacter pylori colonization, glandular atrophy, intestinal metaplasia, gastric ulcer, and gastric carcinoma. Our aim was to clarify whether it is necessary to biopsy the incisura angularis routinely during gastroscopy, in addition to obtaining biopsies of the corpus and antrum. PATIENTS AND METHODS: A total of 272 consecutive patients, with a mean age +/- SD of 53.8 +/- 15.5 years, had two biopsies taken from the angulus, two from the antrum, and two from the corpus of the stomach during routine upper gastrointestinal endoscopy. Histological specimens were examined according to the updated Sydney System for the classification and grading of gastritis. RESULTS: Of the 272 patients, 11 (4.0 %) showed chronic inflammation in the angulus biopsy only. Similarly, the angulus was the only biopsy site which showed neutrophil polymorph infiltration (or "activity") in two patients (0.7 %), intestinal metaplasia in 13 patients (4.7 %), atrophy in three patients (1.1 %), and H. pylori colonization in one patient (0.4 %). Dysplasia (intraepithelial neoplasia) was not found in any of the biopsied sites in any of the 272 patients. H. pylori was found in 39 of the 272 patients (14 %). Of the 272 patients, 120 patients showed abnormalities at the incisura angularis, 101 having gastropathy or erosions, and only 19 showing more specific macroscopic changes, the main ones being ulcer, ulcer scarring, and atrophy. Of the 152 patients with a normal-looking mucosa at the angulus, only six (3.9 %) showed the histological changes of chronic inflammation in the angulus alone. Similarly, the angulus was the only biopsy site which showed neutrophil polymorph infiltration in one patient (1/152, 0.7 %), and intestinal metaplasia in five patients (5/152, 3.3 %). Atrophy and H. pylori colonization were not seen exclusively at the angulus in any of the patients with a macroscopically normal-looking angulus. CONCLUSION: Based on our data, routine biopsy of the incisura angularis would provide little additional clinical information to that obtainable from antrum and corpus biopsies.

Biochemical markers of types I and III collagen and limited joint mobility in type 1 diabetic patients.

Limited joint mobility (LJM), a long-term complication of diabetes, has been shown to be associated with microvascular complications of diabetes. Connective tissue alterations may contribute to the development of LJM and other diabetic complications. We tested whether biochemical markers of types I and III collagen metabolism are associated with LJM in type 1 diabetes. We studied 28 male patients of mean age 43.4 years (SD=9.5) and with a duration of diabetes of 25.2 years (SD=9.7) years. LJM assessment included goniometric measurements of the joints and classification by Rosenbloom's method. We measured serum concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal crosslinked telopeptide of type I collagen (ICTP); urinary excretion of crosslinked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) was also measured. Although average serum PIIINP tended to be higher in subjects with moderate-severe LJM (3.1 +/- 1.3 microg/l) than in subjects with mild LJM (2.5 +/- 0.7 microg/l) or without LJM (2.6 +/- 0.4 microg/l), no significant association was found (p<0.27). Concentrations of the other collagen markers were not different in subjects with or without LJM. We conclude that synthesis and degradation of types I and III collagen in diabetic subjects with LJM did not differ from those without LJM to reflect changes in the biochemical markers of these proteins.

Biochemical markers of type III and I collagen: association with retinopathy and neuropathy in type 1 diabetic subjects.

AIMS: Connective tissue alterations may contribute to the development of diabetic long-term complications in eyes, kidneys and peripheral nerves. Collagen deposition may be increased in micro- and macrovascular disease in diabetic subjects. We tested whether biochemical markers of type III and I collagen metabolism are associated with retinopathy and neuropathy in Type 1 diabetes. METHODS: A total of 28 patients, mean age 43.4 +/- 9.5 (sd) and duration of diabetes 25.2 +/- 9.7 years, were studied. Stereoscopic colour fundus photographs were taken for assessment of retinopathy which was classified as no, background or proliferative. Concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in serum and urinary excretion of cross-linked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) into urine were measured. RESULTS: Average serum PIIINP was higher in subjects with proliferative (3.2 +/- 1.1 microg/l) than without proliferative retinopathy (2.5 +/- 0.6 microg/l) (P = 0.03). Average serum PICP was higher in subjects without retinopathy (181.7 +/- 19.5 microg/l) than in subjects with background retinopathy (132.1 +/- 42.7 microg/l) (P = 0.02). Concentrations of other collagen markers were not different in subjects with or without retinopathy. No association between collagen markers and neuropathy was found. CONCLUSIONS: The increased synthesis of type III collagen, reflecting deposition of matrix and basement membrane connective tissue, may be involved in the pathogenesis of proliferative retinopathy in Type 1 diabetic subjects. On the other hand, we observed decreased synthesis of Type I collagen, which can result in weakened vascular integrity in subjects with retinopathy.

Intestinal type of thromboangiitis obliterans (Buerger disease) preceding symptoms of severe peripheral arterial disease.

The case of a 50-year-old man with intestinal type thromboangiitis obliterans (Buerger disease) is reported. Intestinal manifestations included stricture and perforation of the colon, and these preceded any symptoms of peripheral vascular disease. Only the histological examination was able to show that our patient had the intestinal type of thromboangiitis obliterans.

Diabetic complications are associated with liver enzyme activities in people with type 1 diabetes.

This study was performed to clarify if diabetic complications are associated with liver enzyme activities in type 1 diabetic outpatients. Elevated activities of serum aminotransferases are a common sign of liver disease and are observed more frequently among people with diabetes than in the general population. Many studies have shown an association between specific diabetic complications and disturbances in various tissues, such as diabetic nephropathy and cardiovascular diseases, but only limited data are available on the possible association between diabetic complications and liver function. We studied 28 patients with type 1 diabetes. Mean age was 43.4+/-9.5 (S.D.), and duration of diabetes 25.2+/-9.7. Limited joint mobility (LJM) was assessed by the Rosenbloom's method. Background and proliferative retinopathy, and peripheral symmetrical polyneuropathy were also assessed. Activities of alanine amino transferase (ALT), gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) in serum were determined. The metabolic control of the diabetes was evaluated by the glycosylated haemoglobin A(1c) (HbA(1c)) level and lipid values were also measured. ALT activity was associated with LJM (P<0.01) and with neuropathy (P<0.01). Association between GGT activity and LJM (P<0.01) and neuropathy (P<0.01) were also found. GGT activity was also associated with the severity of retinopathy (P<0.01). None of these associations was explained by confounding effects of diabetes duration, age, body mass index (BMI), HbA(1c) or alcohol consumption. In conclusion, diabetic complications such as LJM, retinopathy and neuropathy are associated with liver enzyme activities independent of alcohol consumption, BMI and metabolic control of diabetes.