Adalimumab biosimilars in the therapy of Crohn´s disease and ulcerative colitis: Prospective multicentric clinical monitoring.

OBJECTIVE: The adalimumab biosimilars FKB327 and GP2017 were approved for the therapy of patients with inflammatory bowel disease (IBD). Relatively few prospective studies with biosimilar adalimumab in patients with IBD have been published. The aim of this prospective observational study was to evaluate the effectiveness and safety of the biosimilar adalimumab. MATERIAL AND METHODS: Adalimumab biosimilars FKB327 (Hulio®) and GP2017 (Hyrimoz®) were indicated to 50 naive patients in terms of biological therapy with Crohn's disease (CD) or ulcerative colitis (UC). Effectiveness of therapy was evaluated via the Crohn's Disease Activity Index [CDAI] or the Mayo Scoring System [MSS] in patients with CD or UC, respectively, before and after 12 weeks. Additional goals were to evaluate weight changes, laboratory tests and complications or adverse events of this therapy. RESULTS: In CD patients, remission (CDAI <150) was achieved in 73.5% of cases, partial response (≥70-point decrease in CDAI score from baseline) in 11.8%, no response in 11.8% and 2.9% patients discontinued therapy. In UC patients, remission (total score on partial Mayo index ≤2 points) was achieved only in 18.8% of cases, partial response (≥2-point decrease in partial Mayo score from baseline) in 43.8%, no response in 25.0% and 12.5% patients discontinued therapy. There were statistically significant improvements in CDAI, MSS, haemoglobin, fecal calprotectin, albumin and CRP serum levels after 12 weeks of therapy. Seven adverse events were identified, three of which resulted in therapy being discontinued. CONCLUSIONS: This prospective observational study proved the effectiveness of the adalimumab biosimilars FKB327 and GP2017 in IBD.

Fecal Microbial Transplantation versus Mesalamine Enema for Treatment of Active Left-Sided Ulcerative Colitis-Results of a Randomized Controlled Trial.

BACKGROUND AND AIMS: Ulcerative colitis (UC) is a chronic inflammatory disease. Fecal microbial transplantation (FMT) is a promising alternative treatment. METHODS: This multicenter, open-label, noninferiority trial randomized patients with active left-sided UC (Mayo score 4-10) equally to FMT or 5-aminosalicylic acid (5-ASA) enemas. FMT enemas were administered five times in the first week and then once weekly for 5 weeks. 5-ASA enemas were administered daily for 2 weeks and then every other day. The primary study endpoint was clinical remission, with a total Mayo score ≤2 at week 12 with no subscore >1. RESULTS: Sixty-one patients were screened; 45 were enrolled and randomized to FMT (n = 23) or 5-ASA (n = 22). Twenty-one FMT and 22 5-ASA patients completed at least the week 4 study visit and were included in the mITT analysis. Twelve FMT (57%) and eight 5-ASA patients achieved the primary study endpoint. FMT noninferiority with 10% margin was confirmed (95% CI: -7.6%, 48.9%). Adverse events occurred in 12 FMT (57%) and 13 5-ASA (59%) patients. Increased microbial diversity persisted 3 months after FMT. CONCLUSION: FMT is an effective treatment for left-sided UC and increased recipient microbiome diversity. Targeted microbiome modification may improve FMT efficacy. Further investigation is needed to guide donor and patient selection.

Characterization of esophageal motor activity, gastroesophageal reflux, and evaluation of prokinetic effectiveness in mechanically ventilated critically ill patients: a high-resolution impedance manometry study.

BACKGROUND: Motility disorders of upper gastrointestinal tract are common in critical illness and associated with significant clinical consequences. However, detailed quantitative and qualitative analyses of esophageal motor functions are lacking. Therefore, we aimed to characterize the key features of esophageal motility functions using high-resolution impedance manometry (HRIM) and to evaluate an objective link between esophageal motor patterns, gastric emptying, and gastroesophageal reflux. We also studied the prokinetic effects of metoclopramide. METHODS: We prospectively performed HRIM for 16 critically ill hemodynamically stable patients. Patients were included if they had low gastric volume (LGV; < 100 mL/24 h, n = 8) or high gastric volume (HGV; > 500 mL/24 h, n = 8). The HRIM data were collected for 5 h with intravenous metoclopramide administration (10 mg) after the first 2 h. RESULTS: The findings were grossly abnormal for all critically ill patients. The esophageal contraction vigor was markedly increased, indicating prevailing hypercontractile esophagus. Ineffective propulsive force was observed for 73% of esophageal activities. Panesophageal pressurization was the most common pressurization pattern (64%). Gastroesophageal reflux predominantly occurred with transient lower esophageal sphincter relaxation. The common features of the LGV group were a hyperreactive pattern, esophagogastric outflow obstruction, and frequent reflux. Ineffective motility with reduced lower esophageal sphincter tone, and paradoxically fewer reflux episodes, was common in the HGV group. Metoclopramide administration reduced the number of esophageal activities but did not affect the number of reflux episodes in either group. CONCLUSION: All critically ill patients had major esophageal motility abnormalities, and motility patterns varied according to gastric emptying status. Well-preserved gastric emptying and maintained esophagogastric barrier functions did not eliminate reflux. Metoclopramide failed to reduce the number of reflux episodes regardless of gastric emptying status. Trial registration ISRCTN, ISRCTN14399966. Registered 3.9.2020, retrospectively registered. https://www.isrctn.com/ISRCTN14399966 .

Acute portal vein thrombosis in noncirrhotic patients - different prognoses based on presence of inflammatory markers: a long-term multicenter retrospective analysis.

Background: Portal vein thrombosis (PVT) is a partial or complete thrombotic occlusion of the portal vein and is rare in noncirrhotic patients.Patients and methods: 78 adult patients with noncirrhotic acute PVT without known malignity were evaluated. Patients with initial CRP level 61-149 mg/l were excluded.Results: Patients were divided into two groups - the first one (33 patients) was characterized with signs of inflammation and CRP over 149 mg/l. The second group (45 patients) was without signs of inflammation and CRP level less than 61 mg/l. The frequency of prothrombotic hematologic factors was statistically significantly different in levels of factor VIII and MTHFR 677 C mutation. All patients from both groups underwent the same oncologic and hemato-oncologic screening which was positive in 23 patients (51.1%) in the group without signs of inflammation. In the group of patients with clinical and laboratory signs of inflammation oncologic and hemato-oncologic screening was positive only in 1 patient (3.0%). Complete portal vein recanalization was achieved in 19.2%, partial recanalization in 26.9%.Conclusions: Patients with clinical signs of inflammation and acute PVT have a low risk of malignancy in contrast to patients without signs of inflammation and acute PVT, which have a high risk of oncologic or hemato-oncologic disease. Patients with negative hemato-oncologic screening should be carefully observed over time because we expect they are at higher risk for the development of hemato-oncologic disease, independent from the presence and number of procoagulation risk factors.

Safety of Anti-TNF-Alpha Therapy During Pregnancy on Long-term Outcome of Exposed Children: A Controlled, Multicenter Observation.

BACKGROUND: Evidence of the impact of in utero exposure to anti-tumor necrosis factor (TNF)-alpha on long-term childhood development is limited. The aim was to assess the impact of in utero exposure to anti-TNF-alpha due to mothers' inflammatory bowel disease (IBD) on long-term postnatal development of exposed children. METHODS: We included consecutive children (≥12 months of age) born to mothers with IBD (2007-2016) treated with anti-TNF-alpha during pregnancy in 3 centers in the Czech Republic. A control group was comprised of unexposed children of non-IBD mothers undergoing mandatory check-ups at general pediatricians' offices. Data on perinatal period, psychomotor development, vaccination, infections, antibiotics, and allergy were collected by treating pediatricians using a predefined questionnaire. RESULTS: Seventy-two exposed and 69 unexposed children were included (median age, 35 and 50 months, respectively). Exposed children had growth and psychomotor development similar to controls. There was no significant difference in infectious complications within the first year of life (23.9% vs 17.4%; P = 0.36) or during the whole follow-up between exposed infants and controls (P = 0.32). Concomitant immunosuppressants during pregnancy and anti-TNF-alpha levels in cord blood were not associated with elevated infection rate within the first year of life (P > 0.05). Over 95% of exposed children had adequate serologic response to vaccination, except for haemophilus and mumps vaccines. Clinically manifested allergy was similar between the groups (P = 0.98). CONCLUSIONS: Anti-TNF-alpha exposure in utero does not seem to have a negative impact on postnatal development of children with regard to infectious complications, allergy, growth, or psychomotor development when compared with unexposed children of non-IBD women.

Diagnosis of gastrointestinal motility disorders.

Gastrointestinal motility and the effects on luminal contents that are brought about by it can be studied in several ways. In clinical practice, manometry remains one of the most important investigational techniques, in particular for oesophageal and anorectal disorders. Radiographic examination of bolus transit through the gastrointestinal tract also continues to be a valuable tool. Scintigraphy still is the standard for assessment of gastric emptying, but 13C breath tests are an alternative. Many other techniques are used mainly in the context of scientific research but some of these may become incorporated in the diagnostic armamentarium. Key words: breath tests - conventional manometry - high-resolution manometry - radiodiagnostic methods - scintigraphy.

[Percutaneous endoscopic gastrostomy: analysis of practice at the endoscopic center of tertiary medical care]. / Perkutánní endoskopická gastrostomie: analýza praxe v endoskopickém centru terciární lékarské péce.

INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is a minimally invasive routine procedure used to provide long-term enteral nutrition in selected patients with impaired oral intake. The knowledge of clinical, technical and safety features of PEG is an important issue in clinical practice.The aim of this study was to evaluate the popu-lation of patients selected for PEG insertion, describe certain aspects of the insertion procedure, assess the service life of PEG, as well as account for the number of complications and patient mortality in the six-month period following the procedure. METHODS: We used a retrospective analysis of data from medical database. The data were collected in a single endoscopic tertiary-referral center for a period of seven and a half years. RESULTS: We evaluated 326 PEG insertions performed on 292 patients with a median age of 63 years (IQR 55-70). Mortality in the six-month period following PEG insertion was 26 %. Prevailing indications for PEG insertion were oncological (53 %) and neurological (40 %) diseases, with certain fluctuation of these numbers during the observed period according to changing demands of the two medical specialties. Local anesthesia alone was applied in 56 % of patients, 38 % underwent analgosedation and 6 % required general anesthesia. Median duration of the procedure (from insertion of endoscope to its final extraction) in 68 consecutive procedures was 6 minutes (IQR 5-8). Median interval between PEG introduction and its first replacement in 21 patients was 22 months (IQR 14-31, range 4-76). 61 patients underwent PEG extraction during the observed period, 66 % of whom had oncological disease. Periprocedural complications were seen in 5.8 % of patients, of these one patient (0.3 %) suffered a serious complication. The buried bumper syndrome was observed in four patients (1.2 %), all of whom had neurological disease. CONCLUSIONS: PEG is a relatively safe procedure and can be performed in a short time using local anesthesia or analgosedation in a majority of patients. The population of patients indicated for PEG insertion reflects primarily the current needs of neurological and oncological departments. Most patients within the observed group benefit from PEG insertion for more than six months. KEY WORDS: analgosedation - complications - mortality - percutaneous endoscopic gastrostomy.

Clinical monitoring: infliximab biosimilar CT-P13 in the treatment of Crohn's disease and ulcerative colitis.

OBJECTIVE: The infliximab biosimilar CT-P13 (Remsima(®), Inflectra(®)) was approved in Europe for the treatment of inflammatory bowel disease (IBD) based on extrapolation of data from patients with rheumatic disease. Because there are limited published reports on clinical outcomes for IBD patients treated with CT-P13, we monitored responses to induction treatment with this biosimilar in patients with Crohn's disease (CD) or ulcerative colitis (UC) in centres across the Czech Republic. MATERIAL AND METHODS: Fifty-two patients with CD (n = 30) or UC (n = 22) were treated with 5 mg/kg CT-P13 for up to 14 weeks. Effectiveness of therapy was evaluated with the Crohn's Disease Activity Index (CDAI) or the Mayo Scoring System (MSS) in patients with CD or UC, respectively, before and after 14 weeks. Additional goals were to evaluate weight changes, serum C-reactive protein (CRP) levels, and complications/adverse events. RESULTS: In patients with CD, remission (CDAI <150) was achieved in 50.0% of cases, and partial response (≥70-point decrease in CDAI score from baseline) in the remaining 50.0%. In patients with UC, remission (total score on partial Mayo index ≤2 points) was achieved in 40.9% of cases, partial response (≥2-point decrease in partial Mayo score from baseline) in 54.5%, and no response in 4.5%. There were statistically significant improvements in CDAI, MSS and CRP serum levels after 14 weeks of therapy, and body weight increased. Four adverse events were identified (n = 1 each): lower-extremity phlebothrombosis, herpes labialis, pneumonia and allergic reaction. CONCLUSIONS: This prospective observational study provides evidence of the effectiveness of CT-P13 in IBD.

[Biological therapy in women with inflammatory bowel disease during pregnancy]. / Biologická terapie u pacientek s idiopatickými strevními zánety v gravidite

The aim of this article is to objective review available research data regarding the safety of biological therapies during pregnancy and breastfeeding in women with inflammatory bowel disease. Biological therapies appear to be safe in pregnancy, as no increased risk of malformations has been demonstrated. Available clinical results suggest that the efficacy of infliximab and adalimumab in achieving clinical response and maintaining remission in pregnant patients might outweigh the theoretical risks of drug exposure to the fetus. If possible, anti-TNF therapy should be stopped by the end of the second trimester due to transplacental transfer and potential risk for the fetus. The use of infliximab and adalimumab is probably compatible with breastfeeding.

Clostridium difficile infection in hospitalized patients at a Czech tertiary center: analysis of epidemiology, clinical features, and risk factors of fulminant course.

OBJECTIVE: Clostridium difficile infection (CDI) has been increasing in incidence, with significant morbidity and mortality, and is subject to geographical and institutional variability. We aimed to characterize epidemiology and clinical manifestations of CDI in a Czech tertiary care center and to identify risk factors of fulminant course. METHODS: All adult patients hospitalized with primary CDI in a 3-year period were retrospectively identified. Epidemiological and clinically descriptive data were extracted from medical records. Multivariate analysis was used to identify the risk factors of fulminant course. The relationship between incidence of CDI and antibiotic consumption was evaluated. RESULTS: Overall, 183 CDI patients, median age 67 years, were enrolled. Hospital-acquired CDI was present in 85% of cases. The incidence of CDI was 1/10,000 patient-days. Hospital-acquired CDI hospital mortality was 22.4%. Severe CDI (SCDI) was identified in 15.8% of patients, with 62% mortality. SCDI patients had longer onset of symptoms to diagnosis interval compared with mild CDI (P=0.05). Multivariate analysis showed that SCDI patients were older (P=0.018), and more frequently had abnormal abdominal physical findings (P=0.001), higher inflammatory markers (P<0.001), higher creatinine (P=0.002), and lower albumin (P<0.001) than patients with mild CDI. Analysis of antibiotic consumption at departments with the highest incidence of CDI showed a trend toward higher incidence of CDI associated with penicillin use (P=0.08) and a negative correlation of CDI incidence with nitroimidazoles consumption (P=0.03). CONCLUSION: CDI is less frequent in the conditions studied compared with literary data; however, the fulminant form has a very high mortality. Delayed recognition and treatment is a crucial determinant of the severity of CDI. The association between CDI and antibiotic consumption is less clear.

Impact of anti-tumor necrosis factor alpha antibodies administered to pregnant women with inflammatory bowel disease on long-term outcome of exposed children.

BACKGROUND: Prenatal exposure to anti-tumor necrosis factor α (TNF-α) antibodies seems to be safe for fetal development. Data on long-term outcome of exposed children are missing. Our aim was to assess long-term postnatal development of children exposed to anti-TNF-α during pregnancy. METHODS: Consecutive children aged ≥ 12 months exposed to anti-TNFs prenatally for maternal inflammatory bowel disease in 3 centers in the Czech Republic were enrolled. Data on psychomotor development, infections, antibiotics, vaccination, and allergy were retrospectively obtained from mothers, treating pediatricians, and children's vaccination cards. Furthermore, standardized laboratory tests on humoral and cellular immunity were performed. RESULTS: Twenty-five children exposed to biologicals were included (median age, 34 mo; range, 14-70 mo). All children had normal growth, and all but 1 had normal psychomotor development. Majority (80%) experienced at least 1 infection (mainly respiratory), and 60% of infants received antibiotics, 32% of those within the first year of life. Vaccination was undertaken according to vaccination protocol to 23 infants (92%). Fifteen children also had tuberculosis vaccination without serious complication. Immunological investigation was performed with 17 children (68%). Cellular immunity was normal in all infants, and 7 children had mild decrease in IgA and/or IgG immunoglobulins without clinical significance. All children had a detectable serologic response to vaccination. CONCLUSIONS: Exposure to anti-TNF-α antibodies seems to be safe for growth and psychomotor development of children, although clinical significance of relatively high frequency of infections and antibiotic use among infants remains questionable because of the lack of a control group. Continuous follow-up of exposed children is absolutely warranted.

Diagnosing celiac disease in patients with a history of lymphoma: factors that matter.

OBJECTIVE: The aim of this study was to identify pitfalls in establishing the diagnosis of celiac disease (CD) in patients with a history of lymphoma. METHODS: A total of 103 patients with a history of lymphoma had anti-tissue transglutaminase antibodies (atTGA) and their class A, G, and M immunoglobulin (IgA, IgG) levels determined. Patients with atTGA positivity underwent enterobiopsy and CD-associated HLA locus testing. RESULTS: The mean age of patients was 55 ( ± 13.5) years. The predominant lymphoma types included B-type non-Hodgkin's lymphoma (B-NHL, 66 %), T-type NHL (8 %), and Hodgkin's lymphoma (26 %). Serological positivity was documented in 3.9 % of cases; one patient had the diagnosis of CD confirmed by enterobiopsy. In 11 patients (10.7 %), IgA levels were decreased to a various extent; of these patients, 10 were shown to have also their IgG levels decreased. The median time from follow-up to blood collection was 58 (32-104) months. The decrease in immunoglobulin levels correlated with a more advanced stage of the tumor (Ann Arbor III-IV) at the time of diagnosis [1.4 (0.9-2.0) g/l versus 2.4 (1.5-3.0) g/l for IgA, p = 0.0001; and 9.4 (7.2-11.5) g/l versus 11.2 (10.3-12.3) g/l for IgG, p = 0.001] and older age [65 (54-72) years versus 55 (44-61) years for IgA, p = 0.04; and 69 (59-74) years versus 53 (43-61) years for IgG, p = 0.0001]. Rituximab therapy in B-NHL patients had no effect on the subsequent incidence of decreased IgA levels. CONCLUSION: Reduced IgA and IgG levels represent important factors contributing to the low detection rate of serological screening for CD in patients with a history of lymphoma.