Pracovní skupina pro idiopatické střevní záněty (PS IBD) České gastroenterologické společnosti přináší v následujícím textu aktualizovaná doporučení pro medikamentózní léčbu ulcerózní kolitidy (UC). Tato doporučení zahrnují přehled léků konvenčních i medikamentů označovaných jako pokročilá (advanced) nebo též cílená léčba. Její rychlý rozvoj v posledních letech dále akceleroval a přinesl nové možnosti pacientům, u nichž konvenční léčiva selhávají nebo nejsou tolerována. Aktualizovaná doporučení jsou ve srovnání s předchozími [1] textem stručnějším a více zaměřeným na praktické informace o léčbě. Užitečnou pomůckou by pro čtenáře měl být závěrečný algoritmus, který shrnuje současné poznatky a zkušenosti expertů PS IBD v oblasti cílené terapie UC. Praktickou stránku textu podtrhuje i rozdělení cílené léčby na léky první linie a vyšších linií tak, jak stanovují aktuální úhradové podmínky Státního ústavu pro kontrolu léčiv (SÚKL). Do textu jsme nezařadili část věnovanou léčbě IBD v graviditě a laktaci, toto téma bude publikováno v samostatném článku v některém z dalších čísel časopisu. Narůstající potřeba moderní léčby spolu s dramaticky stoupajícími počty pacientů s UC v České republice vyžadují zapojení stále většího počtu aktivních gastroenterologů a zájemců o problematiku IBD. Právě jim je následující text určen především.

Background: Inflammatory bowel disease (IBD) is mostly diagnosed in young women of fertile age, and a significant number of patients become pregnant while they have the disease. The remission of the illness, which is often achieved by intensive anti inflammatory treatment, has been found to be the most important factor of a successful pregnancy. Vedolizumab (VDZ) and ustekinumab (UST) are newer types of monoclonal antibodies with different mechanisms of effect when compared to anti-TNF treatment. VDZ is a monoclonal antibody against the α4ß7 integrin receptor, and UST against interleukin 12/23; both have expanded the spectrum of the biological treatment of IBD in recent years. Aims: To present the results of a multicentre observational study. The primary aim was to assess the safety of vedolizumab and ustekinumab for pregnancy, foetal development and the neonatal outcome. The secondary aim was to measure the drug concentration in maternal and cord blood at the time of delivery. Methods: It was a multicentre, retrospective-prospective observational study. Data on patients’ demographics, clinical characteristics and pregnancy were collected by the treating physician using a predefined questionnaire, data on newborn outcome were obtained from medical documentation. The ELISA method was used to measure the VDZ and UST concentrations. Results: The study took place in 15 IBD clinical centres in the Czech Republic. 79 women with 85 completed pregnancies were included in the study, and they were exposed to VDZ or UST during pregnancy. 36 women were treated with vedolizumab (median age 32 years) and 49 with ustekinumab (median age 30.5 years). In the group with VDZ, live births occurred with 32 women (88.9%), and there were two early spontaneous abortions up to the eighth week of gestation in addition to two instrumentally aborted pregnancies (4, 11.1%). 31 children (93.9%) in the group with VDZ were born at term with a median birth weight of 3,097.5 grams. In the ustekinumab group, 39 women (79.6%) had live births, there were nine early abortions and one instrumentally aborted pregnancy (10, 20.4%). 38 (97.4%) children were born at term with a median birth weight of 3,265 grams. The drug levels of VDZ and UST at birth were measured in 44 neonate-mother pairs (21 VDZ, 23 UST). The median level of VDZ in maternal venous blood was 7.2 mg/l, and in cord blood it was 4.7 mg/l (infant / maternal ratio 0.66). With UST, the median maternal level was 4.7 mg/l, and in neonates it was 7.9 mg/l (infant / maternal ratio 1.65). Conclusion: The results found in a group of women that were being treated for IBD and were exposed to at least one dose of biologic treatment with UST or VDZ during pregnancy are consistent with previously published evidence showing no adverse events, and they confirm the safety profile of new biologics in pregnancy. Due to the still limited number of enrolled patients, further studies are needed on the outcomes of pregnancies with new biologics drugs. Keywords vedolizumab, ustekinumab, pregnancy, transplacentární přenos

Introduction: To date, there is not generally accepted and universal indicator of activity, and functional integrity of the small intestine in patients with coeliac disease. The aim of our study was to investigate whether serum concentrations of the non-essential amino acids citrulline and ornithine might have this function. Methods: We examined serum citrulline and ornithine concentrations in a subgroup of patients with proven coeliac disease and healthy controls (blood donors). Results: A total of 94 patients with coeliac disease (29 men, mean age 53 ± 18 years; 65 women, mean age 44 ± 14 years) and 35 healthy controls (blood donors) in whom coeliac disease was serologically excluded (10 men, mean age 51 ± 14 years; 25 women, mean age 46 ± 12 years) were included in the study. Significantly lower concentrations of serum ornithine were found in patients with coeliac disease (mean 65 ± 3 μmol/L; median 63 μmol/L, IQR 34 μmol/L, p < 0.001). No statistically nor clinically significant differences were found in the citrulline concentrations between the study and control group. Conclusions: Serum ornithine (but not citrulline) may be useful for assessing the functional status of the small intestine in uncomplicated coeliac disease. Further studies involving more detailed analysis of dietary and metabolic changes in patients will be needed to reach definitive conclusions.

Background and Aims Evidence on the safety of newer biologics during pregnancy is limited. We aimed to assess the safety of ustekinumab and vedolizumab treatment during gestation on pregnancy and infant outcome. Furthermore, we evaluated the placental transfer of these agents. Methods We performed a prospective, multicentre, observational study in consecutive women with inflammatory bowel disease exposed to ustekinumab or vedolizumab 2 months prior to conception or during pregnancy. Pregnancy, neonatal, and infant outcomes were evaluated and compared with the anti-tumour necrosis factor [TNF]-exposed control group. Drug levels were assessed in maternal and cord blood at delivery. Results We included 54 and 39 pregnancies exposed to ustekinumab and vedolizumab, respectively. In the ustekinumab group, 43 [79.9%] resulted in live births, and 11 [20.4%] led to spontaneous abortion. Thirty-five [89.7%] pregnancies on vedolizumab ended in a live birth, two [5.1%] in spontaneous, and two [5.1%] in therapeutic abortion. No significant difference in pregnancy outcome between either the vedolizumab or the ustekinumab group and controls was observed [p >0.05]. Similarly, there was no negative safety signal in the postnatal outcome of exposed children regarding growth, psychomotor development, and risk of allergy/atopy or infectious complications. The median infant-to-maternal ratio of ustekinumab levels was 1.67 and it was 0.59 in vedolizumab. Conclusions Use of ustekinumab and vedolizumab in pregnancy seems to be safe, with favuorable pregnancy and postnatal infant outcomes. Placental transfer differed between these two drugs, with ustekinumab having similar and vedolizumab having inverse infant-to-maternal ratio of drug levels compared with anti-TNF preparations.

Idiopatické střevní záněty (IBD) jsou imunologicky zprostředkovaná systémová chronická zánětlivá onemocnění. Etiologie obou hlavních zástupců - ulcerózní kolitidy (UC) a Crohnovy choroby (CN) je neznámá a patogeneze obou nemocí je známa jen neúplně. Onemocnění je heterogenní, se širokým spektrem střevních i mimostřevních projevů. Incidence a prevalence idiopatických střevních zánětů vzrůstá a postihuje zejména mladé lidi v reproduktivním věku. Základem diagnózy idiopatických střevních zánětů je detailní anamnéza a kombinace klinických a biochemických vyšetření, vyšetření stolice, endoskopie a zobrazujících radiologických vyšetření (ultrazvuk - UZ, počítačová tomografie - CT a magnetická rezonance - MR). U suspektní IBD je k stanovení diagnózy vyžadována koloskopie s terminální ileoskopií s biopsiemi ze zánětlivě postižené i nepostižené sliznice. Nejčastěji stanovovaný serologický marker je C- reaktivní protein (CRP). Fekální marker kalprotektin (FC) má proti CRP vysokou senzitivitu. Průměrná doba stanovení diagnózy od vzniku symptomů trvá až 10 měsíců. Detailní anamnéza, provedení laboratorního vyšetření se stanovením CRP a fekálního kalprotektinu umožní praktickému lékaři odlišit pacienta s dráždivým tračníkem a správně a včas indikovat koloskopické vyšetření. Zvláštní pozornost je nutné věnovat rizikovým pacientům. U těchto rizikových pacientů je nutno používat časně vysoko účinné léky, aby nedošlo k trvalému poškození trávicí trubice. Tyto vysoce účinné léky - imunosupresiva, biologika a ostatní cílené léky - mohou mít nežádoucí účinky, s jejichž řešením se může praktický lékař setkat.

BACKGROUND:Vedolizumab demonstrated different placental pharmacokinetics than other immunoglobulin G1 antibodies, leading to lower drug levels in cord blood in contrast to maternal blood at the time of delivery. The placental transfer of ustekinumab seems to have a pattern similar to anti-tumour necrosis factor agents. Current evidence on the placental pharmacokinetics of vedolizumab and ustekinumab is limited. We aimed to assess the placental transfer of ustekinumab and vedolizumab in pregnant patients with inflammatory bowel disease.METHODS:Consecutive women from a prospective observational study who were exposed to ustekinumab or vedolizumab within 2 months prior to conception or during pregnancy were included. Ustekinumab and vedolizumab levels were measured in maternal and cord blood at the time of delivery.RESULTS:Drug levels were available in 31 infant-mother pairs (15 exposed to ustekinumab and 16 to vedolizumab). The median maternal and newborn ustekinumab levels were 5.3 mg/l and 10.3 mg/l, respectively (the median infant-to-maternal ratio was 1.7), while the median maternal and cord vedolizumab levels were 7.3 mg/l and 4.5 mg/l (the median infant-to-maternal ratio was 0.66). The ustekinumab levels in cord blood positively correlated with the maternal levels at delivery (ρ = 0.751, p = 0.001). However, no correlation with the timing of the last drug administration was found. In contrast, the vedolizumab levels in cord blood demonstrated significant positive correlation with the maternal levels (ρ = 0.831, p < 0.001) along with the gestational week of the last infusion (ρ = 0.736, p = 0.001).CONCLUSION:Vedolizumab demonstrated different placental pharmacokinetics, leading to lower drug levels in cord blood compared to maternal blood at delivery; in contrast, the placental transfer of ustekinumab seems to have a pattern similar to anti-tumour necrosis factor (TNF) agents.

BACKGROUND:Gastrointestinal injury caused by dextran sodium sulphate (DSS) is a reliable porcine experimental model of inflammatory bowel disease (IBD). The purpose of this study was to evaluate the effect of probiotic Lactobacillus casei DN 114001 (LC) on DSS-induced experimental IBD. RESULTS:Eighteen female pigs (Sus scrofa f. domestica, weight 33-36 kg, age 4-5 months) were divided into 3 groups (6 animals per group): controls with no treatment, DSS, and DSS + LC. LC was administered to overnight fasting animals in a dietary bolus in the morning on days 1-7 (4.5 × 1010 live bacteria/day). DSS was applied simultaneously on days 3-7 (0.25 g/kg/day). On day 8, the pigs were sacrificed. Histopathological score and length of crypts/glands (stomach, jejunum, ileum, transverse colon), length and width of villi (jejunum, ileum), and mitotic and apoptotic indices (jejunum, ileum, transverse colon) were assessed. DSS increased the length of glands in the stomach, length of crypts and villi in the jejunum and ileum, and the histopathological score of gastrointestinal damage, length of crypts and mitotic activity in the transverse colon. Other changes did not achieve any statistical significance. Administration of LC reduced the length of villi in the jejunum and ileum to control levels and decreased the length of crypts in the jejunum. CONCLUSIONS:Treatment with a probiotic strain of LC significantly accelerated regeneration of the small intestine in a DSS-induced experimental porcine model of IBD.

BACKGROUND: Mucosal healing (MH) has become a perspective treatment target in patients with Crohn's disease (CD). Data about the impact of MH on long-term outcome in pediatric patients are still scarce. METHODS: 76 pediatric patients with CD were evaluated retrospectively (2000-2015) in a tertiary care center. Based on MH achievement, they were divided into two groups (MH, n= 17; and No MH, n=59). The primary endpoint was to assess the association of MH and the need for CD-related hospitalizations or surgery in pediatric patients with CD. RESULTS: The number of hospitalized patients was 24% in the MH group and 42% in the No MH group, P = 0.26. The total number of CD-related hospitalizations was not significant between the MH group and the No MH group (5 vs. 41, P = 0.15). The time to the first hospitalization was 24 months in MH and 21 months in No MH, P>0.99. 24% patients in the MH group and 39% patients in the No MH group underwent CD-related operation, P = 0.39. Time to the first operation was 43 months for MH and 19 months for the No MH group, P = 0.13. The follow-up period was 91 months in the MH group and 80 months in the No MH group, P = 0.74. The use of infliximab was positively associated with MH, P = 0.002. CONCLUSIONS: MH was not associated with fewer CD-related hospitalizations or operations in pediatric patients with CD during seven years of follow-up.

BACKGROUND:Memantine, currently available for the treatment of Alzheimer's disease, is an uncompetitive antagonist of the N-methyl-D-aspartate type of glutamate receptors. Under normal physiologic conditions, these unstimulated receptor ion channels are blocked by magnesium ions, which are displaced after agonist-induced depolarization. In humans, memantine administration is associated with different gastrointestinal dysmotility side effects (vomiting, diarrhoea, constipation, motor-mediated abdominal pain), thus limiting its clinical use. Mechanism of these motility disorders has not been clarified yet. Pigs can be used in various preclinical experiments due to their relatively very similar gastrointestinal functions compared to humans. The aim of this study was to evaluate the impact of a single and repeated doses of memantine on porcine gastric myoelectric activity evaluated by means of electrogastrography (EGG).METHODS:Six adult female experimental pigs (Sus scrofa f. domestica, mean weight 41.7±5.0 kg) entered the study for two times. The first EGG was recorded after a single intragastric dose of memantine (20 mg). In the second part, EGG was accomplished after 7-day intragastric administration (20 mg per day). All EGG recordings were performed under general anaesthesia. Basal (15 minutes) and study recordings (120 minutes) were accomplished using an EGG stand (MMS, Enschede, the Netherlands). Running spectral analysis based on Fourier transform was used. Results were expressed as dominant frequency of gastric slow waves (DF) and power analysis (areas of amplitudes).RESULTS:Single dose of memantine significantly increased DF, from basic values (1.65±1.05 cycles per min.) to 2.86 cpm after 30 min. (p = 0.008), lasting till 75 min. (p = 0.014). Basal power (median 452; inter-quartile range 280-1312 μV^2) raised after 15 min. (median 827; IQR 224-2769; p = 0.386; NS), lasting next 30 min. Repetitively administrated memantine caused important gastric arrhythmia. Basal DF after single and repeated administration was not different, however, a DF increase in the second part was more prominent (up to 3.18±2.16 after 15 and 30 min., p<0.001). In comparison with a single dose, basal power was significantly higher after repetitively administrated memantine (median 3940; IQR 695-15023 μV^2; p<0.001). Next dose of 20 mg memantine in the second part induced a prominent drop of power after 15 min. (median 541; IQR 328-2280 μV^2; p<0.001), lasting till 120 min. (p<0.001).CONCLUSIONS:Both single and repeated doses of memantine increased DF. Severe gastric arrhythmia and long-lasting low power after repeated administration might explain possible gastric dysmotility side effects in the chronic use of memantine.

Functional hyposplenism is a condition accompanying many diseases including autoimmune disorders and lymphomas. Hyposplenism is also commonly found in adult coeliac disease (up to 20 % of non-complicated and up to 80 % of complicated disease). Hyposplenism is associated with an increased risk of severe infections ( Streptococcus pneumoniae , Neisseria meningitidis and Haemophilus influenzae ). The aim of this prospective study was to investigate memory B lymphocytes as an indirect biomarker of functional hyposplenism. A total of 42 patients with coeliac disease (11 men, 31 women; mean age 49±14 years) and 10 healthy controls, blood donors (2 men, 8 women; mean age 39±7 years) were enrolled into the study. Nobody underwent previous splenectomy and no individual suffered from immunodeficiency. The DuraClone IM panel was used to identify B lymphocytes subpopulations in peripheral blood samples by flow cytometry Navios (Beckman Coulter) with software analysis using Kaluza version 1.2. Patients with coeliac disease and controls did not differ in basic parameters of leukocyte and total lymphocyte blood count. Switched memory B lymphocytes (CD19+CD27+IgD-), non-switched memory / marginal-zone-like B lymphocytes (CD19+CD27+IgD+) and IgM memory B lymphocytes (CD19+CD27+IgM++) were significantly lower in coeliac disease compared to controls. Follicular (naive) B lymphocytes were not significantly different between coeliac disease and controls. In conclusion, dysfunction of memory B lymphocytes can be responsible for an increased risk of severe bacterial infections in coeliac disease. Patients with coeliac disease with dysfunction of memory B lymphocytes are clearly indicated for anti-pneumococcal vaccination.

Mice were gavaged thrice weekly with water (80uL), GSE (80uL; 400mg/kg), EO (80uL) or combined GSE+EO (160uL).Bodyweight and disease activity index (DAI) were measured daily.Colonoscopies were performed on days 26, 41 and 62. Burrowing occurred on days 5, 19, 26, 40, 47 and 61.Three hours prior to kill (day 63), mice were gavaged with FITC-Dextran for permeability analyses (500mg/kg) and colon was then collected for myeloperoxidase assay (MPO; acute inflammation).P<0.05 was considered significant.Results: AOM/ DSS induced significant bodyweight loss (max -21%) and increased DAI (max 83%) throughout the trial (p<0.05).GSE/EO in AOM/DSS mice resulted in further bodyweight loss compared to GSE (day 62; max -6%) and EO (day 29; max -9%) alone (p<0.05).GSE (-51%), EO (-53%) and GSE/EO (-71%) reduced DAI scores in AOM/DSS mice in all three DSS cycles (p<0.05).GSE/EO in AOM/DSS mice resulted in further reduction in DAI compared to GSE (second cycle; max -71%) and EO (at the end of the trial; max -62%) alone (p<0.05).AOM/DSS mice presented with severe colonoscopically-assessed colitis at all three time-points, which was reduced by GSE (day 62), EO (day 62) and GSE/EO (days 41 and 62; p<0.05).Furthermore, AOM/DSS controls presented with the highest number of colonic tumours, which was reduced by GSE (day 20), EO and GSE/EO (days 20 and 62; p<0.05).EO increased burrowing activity of AOM/DSS mice on day 61 (p<0.05), with no significance observed on other days.MPO was increased in AOM/DSS mice compared to saline controls (p<0.05)with no impact of treatments.In AOM/DSS mice FITC-Dextran levels were increased in controls whilst EO (-58%) and GSE/EO (-77%) reduced levels (p<0.05).Finally, in normal animals, GSE (day 7; max -3%) and GSE/EO (day 53; max -8%) resulted in a minor decrease in bodyweight compared to saline controls (p<0.05).Conclusion: GSE/EO resulted in reduced number of colonic tumours and clinical indicators were improved by GSE, EO and the GSE/EO combination.These results suggest potential for GSE/EO to be therapeutic in CA-CRC management.

Differential diagnosis between benign and malignant biliary stenosis can be difficult in clinical practice. Histology of biopsy specimens is often indeterminate. Laboratory markers (serum bilirubin>75 μmol/L, carbohydrate antigen 19-9>400 U/mL) and the length of stenosis (>15 mm) can be helpful but are not specific enough. The aim of this study was to investigate bile acids in liver bile of patients with benign and malignant biliary stenosis and controls without stenosis. A total of 73 patients entered the study: 7 subjects with benign biliary stenosis (6 men, 1 woman; 68±13 years old), 21 with malignant biliary stenosis (15 men, 6 women; 72±14 years old), and 45 patients without biliary stenosis (22 men, 23 women; 70±13 years old); out of those, 25 subjects have and 20 do not have choledocholithiasis. Twenty-three different bile acids were investigated by high-performance liquid chromatography/mass spectrometry. Serum total bilirubin was significantly higher in patients with malignant biliary stenosis compared with nonstenotic controls (p=0.005). Significant relationship (r>0.7) was found between several pairs of bile acids. Significantly lower bile acid concentrations in malignant biliary stenosis compared to controls without stenosis were found for GLCA (p=0.032), GUDCA (p=0.032), GCDCA (p=0.006), GDCA (p=0.031), GHCA (p=0.005), TUDCA (p=0.044), and TDCA (p=0.036). Significant difference in cholic acid was found between benign and malignant stenosis (p=0.022). Analysis of bile acids might be helpful in the differential diagnosis of malignant and benign biliary stenosis. More patients need to be enrolled in further studies so that the real diagnostic yield of bile acids can be determined.

Objective The epidemiology of uninvestigated dyspepsia was studied in the Czech Republic for the first time in 2001. The aim of the current multicenter prospective study was to evaluate dyspepsia using the same methods in a representative sample of general unselected population from the same geographical areas 10 years later. Participants and methods A total of 38 147 individuals comprised the general population for a random two-step selection process. A total of 1836 participants (863 males and 973 females; aged 5–98 years) took part in the questionnaire-based study. Helicobacter pylori status was investigated in all participants by means of 13 C-urea breath test. Results The overall prevalence of dyspepsia was 2.6% among children and adolescents aged 5–17 years and 16.0% among adults aged 18–98 years. We did not detect any statistically significant sex differences in the prevalence of total dyspepsia or its subtypes. Overall, 2.4% of H. pylori -negative children and adolescents aged less than 18 years reported dyspepsia, and 16.8% of H. pylori -negative adults reported it. Among H. pylori -positive children and adolescents and adults, dyspepsia was present in 8.3 and 15.8%, respectively. Type A dyspepsia (as the only long-lasting symptom) was statistically significantly associated with H. pylori status among children and adolescents. Among adults aged 18 years or older, we noted a lower prevalence of dyspepsia in adults with elementary education compared with university education. Current use of antibiotics was associated with an increased prevalence of dyspepsia in adults. Conclusion Despite the substantial decrease of H. pylori infection in the Czech Republic over the past 10 years, the prevalence and sociodemographic determinants of uninvestigated dyspepsia did not change significantly.

Vedolizumab je humanizovaná monoklonální IgG1 protilátka určená k léčbě nemocných s ulcerózní kolitidou a Crohnovou chorobou. Inhibuje α4β7 integrin, a tak selektivně blokuje přilnutí leukocytů (aktivovaných GIT -tropních lymfocytů) k cévní stěně a migraci do střevní submukózy, a tím brání patologickému zánětu v trávicí trubici. Účinnost vedolizumabu byla prokázána jak ve studiích, tak i v reálné klinické praxi, zejména u ulcerózní kolitidy. Výborný bezpečnostní profil, nový mechanismus účinku a klinická potřeba nové léčby idiopatických střevních zánětů vedla k rychlému zabydlení vedolizumabu v klinické praxi. Klíčová slova: vedolizumab, Crohnova choroba, ulcerózní kolitida, biologická léčba.

Vedolizumab je humanizovana monoklonalni IgG1 protilatka urcena k lecbě nemocných s ulcerozni kolitidou a Crohnovou chorobou. Inhibuje α4β7 integrin, a tak selektivně blokuje přilnuti leukocytů (aktivovaných GIT‑ tropnich lymfocytů) k cevni stěně a migraci do střevni submukozy, a tim brani patologickemu zanětu v travici trubici. Ucinnost vedolizumabu byla prokazana jak ve studiich, tak i v realne klinicke praxi, zejmena u ulcerozni kolitidy. Výborný bezpecnostni profil, nový mechanismus ucinku a klinicka potřeba nove lecby idiopatických střevnich zanětů vedla k rychlemu zabydleni vedolizumabu v klinicke praxi.