Vitamin D levels in IBD: a randomised trial of weight-based versus fixed dose vitamin D supplementation.

Objectives: Body weight is one of the factors affecting blood levels of 25-hydroxyvitamin D (25OHD). The aim of this study was to establish whether a vitamin D (vitD) weight-based dosing is more appropriate to a fixed daily dose in patients with inflammatory bowel disease (IBD).Materials/methods: This was an open label randomised trial. Patients with IBD were assigned to receive oral cholecalciferol at a dose of 28 IU/kg (IU/kg) or 2000 IU per day (IU/day) for 12 weeks during winter months. 25OHD plasma levels and other biochemical parameters were measured at baseline and after supplementation period. The primary outcome measure was 25OHD level after a follow-up period.Results: A total of 173 patients were analysed. The mean BMI was 25.5 ± 5.1 and initial mean 25OHD level was 62.7 ± 25.5 nmol/l. A similar increase (9.7 ± 26.9 vs 9.8 ± 26.7 nmol/l) in 25OHD levels occurred both in IU/kg and IU/day group. The proportion of subjects with normal and sub-normal levels following the substitution was comparable irrespective of body weight. The change in 25OHD level correlated positively only with the dose of vitD (p < .001) and negatively with the baseline 25OHD level (p < .001). A sustained 25OHD level of 75 nmol/l corresponds with a calculated daily vitD dose of 2034 IU.Conclusions: Weight-based dosing of vitamin D is not superior to a fixed dose in order to maintain stable 25OHD levels in IBD patients. Cholecalciferol dose of 2,000 IU/day is safe and sufficient during winter period.

Are changes in the blood count clinically useful marker of azathioprine dose?

INTRODUCTION: The 6-thioguanine nucleotide (6-TGN) level, may be used to estimate dose-adequacy of azathioprine (AZA) therapy. 6-TGN test is not commercially available. The aim of the study was to determine whether a blood cell changes correlate also with the dose of AZA and may serve as a predictor of the dose adequacy (for MCV > 6 fl). METHODS: Retrospective, multicentre study in subjects with IBD treated with azathioprine. Demographic data, leukocyte, platelet counts, erythrocyte (MCV) and thrombocyte (MPV) volume, azathioprine dose, inflammatory activity in the 3rd, 6th and 12th months of treatment and presence of sideropenia were recorded. RESULTS: 103 subjects analysed. To increase the MCV by 6 fl, the AZA dose above 2 mg/kg is needed (p = 0.04). The MCV increases within 165 days (95% CI, 154-181 days, p = 0.002). Sideropenia has no impact on the MCV change. Number of leukocytes and thrombocytes decreases during treatment (p < 0.001). Change in their number as well as MPV, does not correlate with MCV change and is not affected by activity of the inflammation. CONCLUSION: The MCV dynamics (> 6 fl within 6 months) is the only relevant indicator during AZA treatment. Changes in the number of leukocytes, platelets and their volume can not be used to assess the sufficiency of the AZA dose. Sideropenia has no impact on the dynamics of MCV.

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.

Vitamin D supplementation dose needs to be higher in patients with inflammatory bowel disease: interventional study.

INTRODUCTION: Vitamin D (vitD) is a substance with an immunomodulatory effect. Its insufficiency has negative impact also on inflammatory bowel disease (IBD) where it is often present. The recommended daily intake for general population is 600 UI/day (units/day). What is the necessary dose for IBD patients remains unknown. The aim of the study was to verify whether the 2,000 IU/day of vitD is sufficient for maintaining sustained levels in these patients. METHODS: Patients with Crohns disease (CD) or ulcerative colitis (UC) were supplemented orally with 2,000 IU of cholecalciferol daily during winter time. The level of 25-hydroxyvitamin D (25OHD) was established at the beginning of substitution period (October to December) and in Month 4. Demographic data, Ca, P, parathormone levels, dose of vitD used, and patients compliance were observed. RESULTS: 108 patients with CD and UC (71/37) were analysed, out of them 51 females, average age 43.3 ± 16.2 years. The level of 25OHD increased from 60.2 ± 26.5 nmol/l to 68.1 ± 27.1 nmol/l (p < 0.001) during the period with the average substitution dose of vitD 1 858 ± 464 IU/day. 60.2 % of subjects complied with the recommended dosing of vitD. The dose of 1,820 IU vitD/day showed to be sufficient for maintaining sustained levels in the model. No changes of Ca, P serum levels occurred during observation period. CONCLUSIONS: Substitution doses of vitD recommended for general population are insufficient for IBD patients. A dose of up to 2,000/day, which is safe, is necessary to maintain normal levels of 25OHD. Noncompliance with the use of vitD is high.

Adherence, risk factors of non-adherence and patient's preferred treatment strategy of mesalazine in ulcerative colitis: multicentric observational study.

OBJECTIVES: Compliance to therapy is a key factor in the efficacy of treatment in clinical practice. The aim of our study was to evaluate the rate of compliance with mesalazine in patients with ulcerative colitis (UC), to examine risk factors of noncompliance and especially find ways on how adherence can be improved. MATERIALS AND METHODS: A total of 198 outpatients with UC completed two anonymous questionnaires including information on basic demographics, details of patient´s disease and the use of mesalazine medication and quality of life. RESULTS: We found noncompliance (percentage of used medication per day less than 80%) with 5-ASA in 21.2% patients. Our study proved that the education level of patients significantly influenced the compliance of patients using mesalazine. A significant difference (p = .014) was found between the compliance of patients with secondary school education (84.1 ± 16.73) and those with university education (94.1 ± 9.9). The majority of patients preferred mesalazine once daily and are less likely to forget to take medication in the morning. Better quality of life was observed based on our data from WHOQOL-BREF questionnaire in statistically significant way in patients using concomitant therapy of immuosuppressive or biological therapy, lower daily doses and using sachets not tablets. CONCLUSIONS: Our study proved that compliance with mesalazine in patients with UC was related only to education level. If we target mesalazine therapy based on patient's preferences, we can improve the adherence with mesalazine. Our data could be beneficial for the treatment strategy in clinical practice.

A head-to-head comparison of 4-L polyethylene glycol and low-volume solutions before colonoscopy: which is the best? A multicentre, randomized trial.

PURPOSE: The purpose of this study is to compare the efficacy and tolerability of polyethylene glycol (PEG) to sodium picosulfate/magnesium citrate (SPMC) and low-volume polyethylene glycol/ascorbic acid (PEGA) in a single- or split-dose regimen for colonoscopy bowel preparation. METHODS: This was a prospective, randomized, endoscopist-blinded, multicentre study. Outpatients received either PEG or SPMC or PEGA in a single or a split dose before the colonoscopy. Quality and tolerability of the preparation and complaints during preparation were recorded. RESULTS: Nine hundred seventy-three patients were analysed. Satisfactory bowel cleansing (Aronchick score 1 + 2) was more frequent when a split dose was used irrespective of the solution type (PEG 90.1 vs 68.8%, PEGA 86.0 vs 71.6%, SPMC 84.3 vs 60.2%, p < 0.001). SPMC was the best tolerated followed by PEGA (p < 0.006) and PEG as the worst (p < 0.001). Tolerability did not correlate with the regimen and amount of the solution used. Female gender is associated with a higher incidence of nausea, vomiting and pain (p < 0.029). CONCLUSIONS: Both PEG, PEGA and SPMC are fully comparable in terms of colonic cleansing when used in similar regimens. The split-dose preparation is more effective in all agents. SPMC and PEGA are better tolerated than PEG. The preparation regimen and/or the volume do not affect tolerability.

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.

[Effective bowel preparation before coloscopy - low-volume PEG in the divided dose regimen]. / Efektivní príprava streva pred koloskopií - nízkoobjemový PEG v deleném rezimu.

INTRODUCTION: The good and safe bowel cleansing is key to the success of coloscopy. The standard preparation involves 4 l polyethylene glycol (PEG). Now the combination of PEG and ascorbic acid (PEGA) of half the volume is available. Besides the type of product also the time factors which are not clarified, play a role during the bowel preparation. The aim of the study was to compare the efficiency and tolerance of both the agents and evaluate the effect of the time regimen of preparation. METHODS: 380 individuals were included in the evaluation in 4 cohorts which used 4 l PEG (Fortrans) in a single dose or split into 3 + 1 l and PEG + ascorbic acid (Moviprep) split into 1 + 1 l or 2 l one day before examination. RESULTS: There was no difference between the agents as to the quality of bowel preparation, when they were used in the same regimen. The bowel cleansing was better in both cases in the divided dose regimen (p < 0.001), and it was inversely proportional to the length of preparation (p = 0.003) and directly proportional to the length of time between the end of preparation and coloscopy (p < 0.001). PEGA was better tolerated (p < 0.028), regardless of the preparation regimen. CONCLUSION: PEG and PEGA are similarly efficient in the bowel preparation before coloscopy provided they are used in a similar regimen. The best results are reached when the preparation is divided into 2 days. PEGA is better tolerated than PEG, regardless of the used regimen. The quality of bowel cleansing is affected by the length of preparation (optimally up to 12 hours) and the time elapsed from the preparation until examination (up to 8 hours).

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.

The optimal bowel preparation intervals before colonoscopy: A randomized study comparing polyethylene glycol and low-volume solutions.

BACKGROUND & AIMS: The optimal duration of bowel preparation has only been assessed for polyethylene glycol (PEG). The aim of the study was to determine the intervals for achieving a satisfactory quality/tolerability of the preparation using PEG/ascorbic acid (PEGA) and sodium picosulphate/magnesium citrate (SPMC), and to compare them with 4L of PEG. METHODS: A randomized, endoscopist-blinded, multicentre study. The 612 outpatients referred to a colonoscopy, were prepared using PEG, SPMC, PEGA. The quality, tolerability, duration of the preparation, and the interval from the end of the preparation to the colonoscopy was assessed. RESULTS: Optimum duration of the preparation was similar for both PEG and SPMC (≥7.3 vs. ≥8.8 h, overall ≥8.4 h). Optimum interval to the colonoscopy was ≤11.8 h and did not differ between preparations (PEG, PEGA ≤ 11.8, SPMC ≤ 13.3 h). These times were the only predictors for a satisfactory preparation. The tolerability depends on the product type (SPMC) only. Timing of the preparation or the other factors had no impact on tolerability. CONCLUSION: The optimum intervals for bowel preparation are identical for all preparations. Satisfactory preparation is achived at the preparation length ≥8.4 h and the time to colonoscopy ≤11.8 h.

Natalizumab for active Crohn's disease.

BACKGROUND: In chronic inflammatory conditions such as Crohn's disease, the migration of leukocytes from the circulation into the parenchyma and their activation within inflammatory sites are mediated in part by alpha4 integrins. METHODS: We conducted a double-blind, placebo-controlled trial of the alpha4 integrin-specific humanized monoclonal antibody natalizumab in 248 patients with moderate-to-severe Crohn's disease. Patients were randomly assigned to receive one of four treatments: two infusions of placebo; one infusion of 3 mg of natalizumab per kilogram of body weight, followed by placebo; two infusions of 3 mg of natalizumab per kilogram; or two infusions of 6 mg of natalizumab per kilogram. Infusions were given four weeks apart. Outcomes included changes in scores for the Crohn's Disease Activity Index (higher scores indicate more severe disease), the health-related quality of life, and C-reactive protein levels. RESULTS: The group given two infusions of 6 mg of natalizumab per kilogram did not have a significantly higher rate of clinical remission (defined by a score of less than 150 on the Crohn's Disease Activity Index) than the placebo group at week 6 (the prospectively defined primary end point in the efficacy analysis). However, both groups that received two infusions of natalizumab had higher remission rates than the placebo group at multiple time points. Natalizumab also produced a significant improvement in response rates (defined by a reduction of at least 70 points in the score on the Crohn's Disease Activity Index). The highest remission rate was 44 percent and the highest response rate was 71 percent (at week 6 in the group given two infusions of 3 mg per kilogram). Overall, the two infusions of 6 mg of natalizumab per kilogram and of 3 mg per kilogram had similar effects. The quality of life improved in all natalizumab groups; C-reactive protein levels improved in groups receiving two infusions of natalizumab. The rates of adverse events were similar in all four groups. CONCLUSIONS: Treatment with the selective adhesion-molecule inhibitor natalizumab increased the rates of clinical remission and response, improved the quality of life and C-reactive protein levels, and was well tolerated in patients with active Crohn's disease.

Poorly differentiated endocrine carcinoma and intraductal papillary-mucinous neoplasm of the pancreas: Description of an unusual case.

Neuroendocrine tumors and intraductal papillary-mucinous neoplasms constitute histologically distinctive but relatively rare entities among pancreatic tumors. Collision of these tumors is extremely rare and causes several diagnostic problems regarding the histopathologic differential diagnosis of other pancreatic epithelial tumors. The question of whether the neoplastic populations originate from common progenitor cell or whether they represent only a fortuitous association has not been sufficiently explained. Here, we describe a new case of poorly differentiated endocrine carcinoma combined with an intraductal papillary-mucinous neoplasm. To disclose the relationship between the two histologic components, neuroendocrine differentiation was studied by confocal laser scanning microscopy using double immunofluorescence labeling with chromogranin-A and CD57 antibodies. Our results revealed a co-localization of both antigens in neuroendocrine cells of the intraductal papillary-mucinous neoplasm. The finding has previously been described in non-neoplastic neuroendocrine cells. Cells forming poorly differentiated endocrine carcinoma showed a wide heterogeneity in immunoreactions. Our results do not indicate a potential histogenetic similarity between these two neoplasms, which are dissimilar histologically, and underline the previous thesis that cells in intraductal papillary-mucinous neoplasm revealing neuroendocrine differentiation represent only a non-neoplastic cell admixture.

Expression of 11ß-hydroxysteroid dehydrogenase type 2 is deregulated in colon carcinoma.

Although the effects of glucocorticoids on proliferation, differentiation and apoptosis are well known, and steroid hormones have been identified to play a role in pathogenesis and the development of various cancers, limited data are available regarding the relationship between the local metabolism of glucocorticoids and colorectal adenocarcinoma (CRC) formation. Glucocorticoid metabolism is determined by 11ß-hydroxysteroid dehydrogenases type 1 and 2 (11HSD1, 11HSD2), which increase the local concentration of cortisol due to the reduction of cortisone, or decrease this concentration due to the oxidation of cortisol. The objective of this study was to evaluate the extent of 11HSD1 and 11HSD2 mRNA in pre-malignant colorectal polyps and in CRC. The specimens were retrieved from patients by endoscopic or surgical resection and the expression of 11HSD1 and 11HSD2 was measured by real-time PCR. The polyps were of the following histological types: hyperplastic polyps and adenomas with low- or high-grade dysplasia. The neoplastic tissue of CRC obtained during tumor surgery was also studied. It was found that 11HSD2 was not only downregulated in CRC but already in the early stages of neoplastic transformation (adenoma with low-grade dysplasia). In contrast, the level of 11HSD1 was significantly increased in CRC but not in pre-malignant polyps. The results demonstrate that the downregulation of 11HSD2 gene expression is a typical feature of the development of colorectal polypous lesions and their transformation into CRC.

Multiple adenomatous duodenal polyposis.

Multiple duodenal polyps are a relatively rare finding, usually co-occurrent with familial adenomatous polyposis (FAP).We report a patient with multiple duodenal adenomas and a negative examination for FAP: multiple flat polyps were detected endoscopically in a 37-year-old male patient, extending from the apex of the bulb to the end of the descending part of the duodenum. In terms of histology, they were tubular adenomas with moderate dysplasia. Colonoscopy and enteroclysis were normal. Both push and capsule enteroscopy only showed multiple polyps in the area of the descending duodenum. DNA analysis of the APC gene was as follows: DGGE, exon 1-15, deletion at codons 1309 and 1061 by means of PCR for attenuated APC were negative. Afterwards we screened the patient for germline MYH mutations using the denaturing high-performance liquid chromatography (DHPLC) in combination with sequencing. No novel pathogenic mutation has been identified. Large polyps were removed by means of endoscopic polypectomy and mucosectomy, while small polyps were removed by means of argon plasma coagulation.We conduct yearly checkups, removing only sporadic polyps. The rare finding of duodenal polyposis not co-occurrent with FAP proves that multiple adenomas in the digestive tube need not necessarily co-occur with FAP.