Milan Lukas

Publications of Milan Lukas

• Results of the 2nd scientific workshop of the ECCO (IV): Therapeutic strategies to enhance intestinal healing in inflammatory bowel disease.

  Authors: Alessandro Armuzzi, Gert Van Assche, Walter Reinisch, Guillaume Pineton de Chambrun, Anne Griffiths, Malgorzata Sladek, Jan C Preiss, Milan Lukas, Geert D'Haens

  Journal of Crohn's & colitis. 03/2012;

  Evidence supporting the importance of assessment of mucosal healing in inflammatory bowel disease has increased in the last years. Mucosal healing has been integrated in the assessment of treatmentEvidence supporting the importance of assessment of mucosal healing in inflammatory bowel disease has increased in the last years. Mucosal healing has been integrated in the assessment of treatment efficacy in ulcerative colitis, but in Crohn's disease this thought has arised after biological agents have been evaluated in clinical trials. Although a validated definition of mucosal healing still does not exist, its use is also assuming an increasingly important role in the follow-up of individual patients in clinical practice. Corticosteroids induce mucosal healing in a small proportion of patients with Crohn's disease and are of no benefit to maintain it. By contrast, mucosal healing in Crohn's disease can be achieved and maintained, with varying degrees of evidence and success, with thiopurines and biological agents. In ulcerative colitis, the ability of corticosteroids to induce mucosal healing is well recognized. 5-aminosalicylates, thiopurines and biological agents are also able to induce mucosal healing and, additionally, to maintain it. Mucosal healing assessment should be considered in clinical practice when symptoms persist despite therapy or when treatment discontinuation is being considered. Conversely, in patients whose clinical remission is not associated with mucosal healing, intensification of treatment is not currently recommended because of lack of evidence.

• Two independent genetic factors responsible for the associations of the IBD5 locus with Crohn's disease in the Czech population.

  Authors: Ondrej Hradsky, Petra Dusatkova, Martin Lenicek, Jiri Bronsky, Dana Duricova, Jiri Nevoral, Libor Vitek, Milan Lukas, Ondrej Cinek

  Inflammatory bowel diseases. 07/2011; 17(7):1523-9.

  The role of the IBD5 locus in development of Crohn's disease (CD) has not been clarified. In the Czech population we examined its genetic association using variants of the SLC22A4 (rs1050152),The role of the IBD5 locus in development of Crohn's disease (CD) has not been clarified. In the Czech population we examined its genetic association using variants of the SLC22A4 (rs1050152), SLC22A5 (rs2631367), two single nucleotide polymorphisms (SNPs) shown to be associated with CD in genome-wide studies (rs6596075 and rs2188962), and four SNPs previously shown to tag the haplotype blocks 4, 7, 9, 10 of the IBD5 locus (IGR2063b_1, IGR2230a_1, IGR100Xa_1, IGR3236a_1). The genotype, phenotype, and allelic frequencies were compared between 469 unrelated patients with CD (177 pediatric-onset, 292 adult-onset) and 470 unrelated healthy controls, all Caucasians of Czech ancestry. The most significant difference between patients and controls was found for the SNP rs6596075 (odds ratio [OR] = 0.70 for the G allele; 95% CI 0.52-0.94) in the dominant model and SNP IGR2063b_1 (OR = 1.38 for the G allele; 95% CI 1.14-1.67) in the log-additive model. We found a strong linkage disequilibrium across the IBD5 locus except rs6596075. The haplotype consisting of minor alleles of all tested SNPs except rs6596075 was carried by 31% patients and 23% control subjects (OR = 1.35, 95% CI 1.06-1.72). The association of variants in SLC22A4 and SLC22A5 was dependent on this risk haplotype, while the strong association of the rs6596075 was seemingly independent. In the analysis of subphenotypes we found only an association of the penetrating disease with rs6596075 (OR = 2.13; 95% CI 1.31-3.47). Our study confirms the importance of IBD5 in determining CD susceptibility, and demonstrates that two independent genetic factors may be responsible for the association observed within this locus.

• The clinical implication of drug dependency in children and adults with inflammatory bowel disease: a review.

  Authors: Dana Duricova, Natalia Pedersen, Martin Lenicek, Christian Jakobsen, Milan Lukas, Vibeke Wewer, Pia Munkholm

  Journal of Crohn's & colitis. 04/2011; 5(2):81-90.

  Drug dependency in adult and paediatric patients with inflammatory bowel disease (IBD) is described and the significance of this response pattern in clinical practice discussed in this review.Drug dependency in adult and paediatric patients with inflammatory bowel disease (IBD) is described and the significance of this response pattern in clinical practice discussed in this review. Dependent patients maintain remission while on the treatment, but they relapse shortly after drug cessation or dose decrease. However, a quick restoration of remission and sustained response is achieved when the therapy is re-introduced or dose increased. Population-based studies have demonstrated that 22-36% of adults and 14-50% of children become corticosteroid dependent. Approximately 1/4-1/3 of treated patients undergo surgery ≤1 year after treatment start, although newer paediatric studies reported lower risk of surgery (5-11%), including dependent patients. The frequent use of immunosuppressants (68-80% of children) might explain this favourable outcome and thus reduce importance of the term corticosteroid dependency. Infliximab dependency was described in 42-66% of children and 29% of adults with Crohn's disease. The risk of surgery 50 and 40 months after treatment start was 10% and 23% in infliximab dependent children and adults, respectively. Maintenance of infliximab in dependent patients was suggested to postpone if not avoid the need of surgery. Lastly, mesalazine dependency was identified in 23% of adults with Crohn's disease. These patients were characterized by mild disease course and lower surgical risk compared to non-responders to mesalazine (32 vs. 61%). Identification of drug dependency is useful for prediction of a certain disease course and surgery. An adjustment of medical therapy may alter the prognosis and disease course.

• Safety and efficacy of the immunosuppressive agent 6-tioguanine in murine model of acute and chronic colitis.

  Authors: Miloslav Kverka, Pavel Rossmann, Helena Tlaskalova-Hogenova, Klara Klimesova, Bindia Jharap, Nanne K de Boer, Rene M Vos, Adriaan A van Bodegraven, Milan Lukas, Chris J Mulder

  BMC gastroenterology. 01/2011; 11:47.

  Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine theOral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD. We induced acute or chronic colitis in BALB/c mice by one or four cycles of 3% dextran sulphate sodium (DSS), respectively. Mice were treated by daily gavages of various dosages of 6-tioguanine, azathioprine, or by phosphate buffered saline (PBS) starting the first day of DSS or after two cycles of DSS, respectively. We monitored the efficacy and toxicity by measuring the weight change and serum alanine aminotransferase (ALT) activity and by disease severity and histology, at the end of the experiment. Moreover, we measured cytokine production after colon fragment cultivation by enzyme-linked immunoabsorbent assay and numbers of apoptotic cells in the spleen by flow cytometry. 6-TG is effective in the treatment of acute DSS-induced colitis in a dose-dependent manner and 40 μg of 6-TG is significantly more effective in the treatment of acute colitis than both AZA and PBS. This effect is accompanied by decrease of IL-6 and IFN-γ production in colon. We did not observe histological abnormalities in liver samples from control (PBS) or 6-TG treated mice. However, liver samples from most mice treated with AZA showed mild, yet distinct signs of hepatotoxicity. In chronic colitis, all thiopurine derivatives improved colitis, 20 μg of 6-TG per dose was superior. High doses of 6-TG led to significant weight loss at the end of the therapy, but none of the thiopurine derivatives increased levels of serum ALT. Both thiopurine derivatives reduced the proportion of apoptotic T helper cells, but a high production of both IL-6 and TGF-β was observed only in colon of AZA-treated mice. Use of 6-TG in the treatment of experimental colitis in mice appears superior to AZA administration and placebo. In contrast to 6-TG, the use of AZA resulted in histological liver abnormalities.

• NKX2-3 and IRGM variants are associated with disease susceptibility to IBD in Eastern European patients.

  Authors: Nora Meggyesi, Lajos S Kiss, Magdalena Koszarska, Martin Bortlik, Dana Duricova, Laszlo Lakatos, Tamas Molnar, Martin Leniček, Libor Vítek, Istvan Altorjay, Maria Papp, Zsolt Tulassay, Pal Miheller, Janos Papp, Attila Tordai, Hajnalka Andrikovics, Milan Lukas, Peter Laszlo Lakatos

  World journal of gastroenterology : WJG. 11/2010; 16(41):5233-40.

  To investigate variants of immunity-related GTPase family M (IRGM) and NKX2-3 genes and genotype-phenotype in Eastern European patients with inflammatory bowel disease (IBD). We analyzed 1707To investigate variants of immunity-related GTPase family M (IRGM) and NKX2-3 genes and genotype-phenotype in Eastern European patients with inflammatory bowel disease (IBD). We analyzed 1707 Hungarian and Czech subjects with Crohn's disease (CD) (n = 810, age: 37.1 ± 12.6 years, duration: 10.7 ± 8.4 years) and ulcerative colitis (UC) (n = 428, age: 43.7 ± 15.0 years, duration: 12.6 ± 9.9 years), as well as 469 healthy controls. IRGM rs13361189, NKX2-3 rs10883365 and ECM1 rs13294 polymorphisms were tested by LightCycler allele discrimination. Detailed clinical phenotypes were determined by reviewing the medical charts. NKX2-3 rs10883365 variant allele was associated with increased risk for CD (P = 0.009, OR = 1.24, 95% CI = 1.06-1.48) and UC (P = 0.001, OR = 1.36, 95% CI = 1.13-1.63), whereas variant IRGM allele increased risk for CD (P = 0.029, OR = 1.36, 95% CI = 1.03-1.79). In contrast, ECM1 rs13294 was not associated with either CD or UC. In CD, the variant IRGM allele was associated with a colon-only location (P = 0.02, OR = 1.62, 95% CI = 1.07-2.44), whereas in UC, the ECM1 variant was associated with cutaneous manifestations (P = 0.002, OR = 3.36, 95% CI = 1.48-7.63). Variant alleles did not predict resistance to steroids or azathioprine, efficacy of infliximab, or need for surgery. NKX2-3 and IRGM are susceptibility loci for IBD in Eastern European patients. Further studies are needed to confirm the reported phenotype-genotype associations.

• Bile acid malabsorption in inflammatory bowel disease: assessment by serum markers.

  Authors: Martin Lenicek, Dana Duricova, Viktor Komarek, Bronislava Gabrysova, Milan Lukas, Zdenek Smerhovsky, Libor Vitek

  Inflammatory bowel diseases. 11/2010; 17(6):1322-7.

  Bile acid malabsorption (BAM) is a common feature of Crohn's disease (CD). We aimed to determine whether BAM develops only in patients with a resected distal ileum or if it also occurs in patientsBile acid malabsorption (BAM) is a common feature of Crohn's disease (CD). We aimed to determine whether BAM develops only in patients with a resected distal ileum or if it also occurs in patients who have not undergone surgery for CD. The study included 347 patients with CD or ulcerative colitis (UC) and 119 healthy subjects (controls). BAM was assessed by measurement of serum levels of 7α-hydroxycholest-4-en-3-one (C4) and fibroblast growth factor 19 (FGF19). We surveyed members of the European Crohn's and Colitis Organization and International Organization for the Study of Inflammatory Bowel Disease to collect current information about BAM diagnosis. The severity of BAM was associated with resection of the distal ileum. Compared with controls, patients who received moderate or extensive ileal resection had significantly increased levels of serum C4 (12 versus 62 versus 243 μg/L, respectively; P < 0.001). However, BAM was also present in a substantial number of the patients with CD who were not treated by surgery who had ileitis or colitis (14% and 11%, respectively). There was an indirect, proportional relationship between levels of C4 and FGF19 (P < 0.001). The most severe BAM occurs in CD patients after resection of the distal ileum, but BAM can occur in surgically untreated CD patients, regardless of disease localization. Laboratory tests for BAM should become a part of the algorithm for diagnosis of CD to identify patients who might respond to therapies such as bile acid sequestrants. FGF19 appears to be a reliable marker of BAM.

• Infliximab dependency is related to decreased surgical rates in adult Crohn's disease patients.

  Authors: Natalia Pedersen, Dana Duricova, Martin Lenicek, Margarita Elkjaer, Martin Bortlik, Paal Skytt Andersen, Libor Vitek, Bogi Davidsen, Vibeke Wewer, Milan Lukas, Pia Munkholm

  European journal of gastroenterology & hepatology. 10/2010; 22(10):1196-203.

  Infliximab dependency in children with Crohn's disease (CD) has recently been described and found to be associated with a decreased surgery rate. To assess infliximab dependency of adult CD patients,Infliximab dependency in children with Crohn's disease (CD) has recently been described and found to be associated with a decreased surgery rate. To assess infliximab dependency of adult CD patients, evaluate the impact on surgery, and search for possible clinical and genetic predictors. Two hundred and forty-five CD patients treated with infliximab were included from Danish and Czech Crohn Colitis Database (1999-2006). Infliximab response was assessed as immediate outcome, 1 month after infliximab start: complete, partial, and no response. Three months outcome, after last intended infusion: prolonged response (maintenance of complete/partial response), infliximab dependency (relapse requiring repeated infusions to regain complete/partial response or need of infliximab >12 months to sustain response). Forty-seven percent obtained prolonged response, 29% were infliximab dependent and 24% nonresponders. The cumulative probability of surgery 40 months after infliximab start was 20% in prolonged responders, 23% in infliximab-dependent patients and 76% in nonresponders (P<0.001). The cumulative probability of surgery at 40 months in patients on maintenance versus on demand regime was 33 and 31%, respectively (P=0.63). No relevant clinical or genetic predictors were identified. The infliximab dependency response seems to be equivalent to the prolonged response in adult CD patients when comparing surgery rates.

• Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn's disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy, multicentre trial.

  Authors: Walter Reinisch, Sieglinde Angelberger, Wolfgang Petritsch, Olga Shonova, Milan Lukas, Simon Bar-Meir, Alexander Teml, Elke Schaeffeler, Matthias Schwab, Karin Dilger, Roland Greinwald, Ralph Mueller, Eduard F Stange, Klaus R Herrlinger

  Gut. 06/2010; 59(6):752-9.

  The aim of the study was to compare azathioprine versus mesalazine tablets for the prevention of clinical recurrence in patients with postoperative Crohn's disease (CD) with moderate or severeThe aim of the study was to compare azathioprine versus mesalazine tablets for the prevention of clinical recurrence in patients with postoperative Crohn's disease (CD) with moderate or severe endoscopic recurrence. This was a 1 year, double-blind, double-dummy, randomised study which took place in 21 gastroenterology centres in Austria, the Czech Republic, Germany and Israel. The study participants were 78 adults with CD who had undergone resection with ileocolonic anastomosis in the preceding 6-24 months without subsequent clinical recurrence and with a Crohn's disease activity index (CDAI) score <200, but with moderate or severe endoscopic recurrence. The study drugs were azathioprine 2.0-2.5 mg/kg/day or mesalazine 4 g/day over 1 year. The primary end point was therapeutic failure during 1 year, defined as a CDAI score > or = 200 and an increase of > or = 60 points from baseline, or study drug discontinuation due to lack of efficacy or intolerable adverse drug reaction. Treatment failure occurred in 22.0% (9/41) of azathioprine-treated patients and 10.8% (4/37) of mesalazine-treated patients, a difference of 11.1% (95% CI -5.0% to 27.3%, p=0.19). Clinical recurrence was significantly less frequent with azathioprine versus mesalazine (0/41 (0%) vs 4/37 (10.8%), p=0.031), whereas study drug discontinuation due to adverse drug reactions only occurred in azathioprine-treated patients (9/41 (22.0%) vs 0%, p=0.002). The proportion of patients showing > or = 1 point reduction in Rutgeerts score between baseline and month 12 was 63.3% (19/30) and 34.4% (11/32) in the azathioprine and mesalazine groups, respectively (p=0.023). In this population of patients with postoperative CD at high risk of clinical recurrence, superiority for azathioprine versus mesalazine could not be demonstrated for therapeutic failure.

• The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations.

  Authors: Gert Van Assche, Axel Dignass, Walter Reinisch, C Janneke van der Woude, Andreas Sturm, Martine De Vos, Mario Guslandi, Bas Oldenburg, Iris Dotan, Philippe Marteau [......] Andrew Cole, Gottfried Novacek, Max Reinshagen, Epameinondas Tsianos, Klaus Herrlinger, Yoram Bouhnik, Ralf Kiesslich, Eduard Stange, Simon Travis, James Lindsay

  Journal of Crohn's & colitis. 02/2010; 4(1):63-101.

• Inflammatory bowel disease as a risk factor for colorectal cancer.

  Authors: Milan Lukas

  Digestive diseases (Basel, Switzerland). 01/2010; 28(4-5):619-24.

  Patients with long-term inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's colonic disease (CD) have an increased risk of colorectal carcinoma (CRC). Eaden's meta-analysis hasPatients with long-term inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's colonic disease (CD) have an increased risk of colorectal carcinoma (CRC). Eaden's meta-analysis has shown that the risk for CRC in UC patients is 2% at 10 years, 8% at 20 years and 18% at 30 years of disease duration. It is now accepted that the risk of colorectal cancer is equivalent in both (UC and CD) conditions. Duration of disease is recognized to be the most important risk factor for CRC development. Extent of disease in another major risk factor. Most cancers arise in patients with extensive disease, which is generally defined as extension of inflammation beyond the hepatic flexure. It was demonstrated that proctitis and proctosigmoiditis posed no increased risk for patients with UC. Recent data from case control studies suggests that greater degrees of colonoscopic or histologically active inflammation are associated with an increased risk of CRC. Recently, it has been proven that shortened tubular colon, colonic stricture and postinflammatory polyps should be considered strong risk factors for CRC development. Primary sclerosing cholangitis (PSC) in patients with UC is associated with substantial risk of CRC. Screening colonoscopy should be performed in patients with UC after 8-10 years of disease. The interval between surveillance examinations is dependent on each individual's personal risk factors. In patients with a previous history of PSC, ongoing active inflammation, previous history of dysplasia or strictures, and strong family history of bowel cancer, annual surveillance is recommended. Colectomy is strictly recommended for patients who were diagnosed with flat high-grade dysplasia (HGD) or CRC and where the diagnosis was confirmed by expert gastrointestinal pathologists. In patients with a biopsy specimen considered indefinite for dysplasia, guidelines suggest colonoscopy between 3 and 12 months. Multifocal low-grade dysplasia (LGD) is a stronger indication for colectomy. The optimal colonoscopic surveillance interval for patients who were diagnosed with a flat LGD is still unknown, but 3-6 months is often recommended. Chemopreventive agents should be used to minimize the risk of developing dysplasia or CRC in IBD patients. It has been shown that mesalazine has a preventive effect for CRC and dysplasia.

• The CTLA4 variants may interact with the IL23R- and NOD2-conferred risk in development of Crohn's disease.

  Authors: Ondrej Hradsky, Petra Dusatkova, Martin Lenicek, Jiri Bronsky, Jiri Nevoral, Libor Vitek, Milan Lukas, Ivana Zeniskova, Ondrej Cinek

  BMC medical genetics. 01/2010; 11:91.

  The CTLA4 (cytotoxic T-lymphocyte antigen 4) gene is associated with several immunopathologic diseases and because of its important immuno-regulatory role it may be considered also a plausibleThe CTLA4 (cytotoxic T-lymphocyte antigen 4) gene is associated with several immunopathologic diseases and because of its important immuno-regulatory role it may be considered also a plausible candidate for a genetic association with inflammatory bowel diseases. Previously published studies found no association of CTLA4 with Crohn's disease itself, but some indicated an association with its subphenotypes. The aim of this study was to assess the association in the Czech population, using a set of markers shown to associate with other diseases. Six polymorphisms within the CTLA4 region were investigated in 333 patients with Crohn's disease and 482 unrelated healthy controls, all Caucasians of Czech origin. The genotypes of the SNPs were determined using the TaqMan SNP genotyping assays. Haplotypes were reconstructed using an expectation-maximization algorithm, and their association with the condition was assessed using log-linear modeling. Then, potential interactions were tested between the CTLA4 variants and other genetic factors known to confer the disease susceptibility. No crude associations with Crohn's disease were found for the tested CTLA4 variants under the log-additive or dominant models. However, when stratified for the genetic risk conferred by the variants in the NOD2 (the p.Leu1007fsX1008, rs5743293) or the IL23R (p.R381Q, rs11209026), a significant negative association emerged for the minor alleles of CTLA4 CT60 (rs3087243), JO31 (rs11571302), JO27-1 (rs11571297) polymorphisms. This negative association with CTLA4 was apparent only in the strata defined by presence minor alleles at the NOD2 rs5743293 (here the CTLA4 CT60 A coffered an OR = 0.43, 95%CI 0.19 - 0.95 for the presence of CT60 A), or IL23R rs11209026 (here the OR for presence of CT60 A was 0.23, 95%CI 0.07 - 0.71). We observed this effect also for the haplotype consisting of minor alleles of the three tightly linked CTLA4 markers. Furthermore, this haplotype was associated with the younger age at diagnosis (OR 1.52, 95%CI 1.09 - 2.11, p = 0.014). A protective effect of a CTLA4 haplotype was unmasked after stratification for the risk variants in the NOD2 and IL23R genes, and may point towards the biological relevance of the molecule in the pathogenesis of the disease.

• Anticarbohydrate antibodies as markers of inflammatory bowel disease in a Central European cohort.

  Authors: Karin Malickova, Peter Lakatos, Martin Bortlik, Viktor Komarek, Ivana Janatkova, Milan Lukas

  European journal of gastroenterology & hepatology. 11/2009;

  BACKGROUND: The study discusses the role of antichitobioside carbohydrate antibody (ACCA), antilaminaribioside carbohydrate antibodies (ALCA), and antimannobioside carbohydrate antibodies (AMCA) inBACKGROUND: The study discusses the role of antichitobioside carbohydrate antibody (ACCA), antilaminaribioside carbohydrate antibodies (ALCA), and antimannobioside carbohydrate antibodies (AMCA) in Central European patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: Twohundred and seventy-two serum samples were used - 116 Crohn's disease (CD), 84 ulcerative colitis, and 72 healthy control samples. All samples were evaluated using enzyme-linked immunosorbent assay for the following four anticarbohydrate assays: ACCA, ALCA, AMCA, and anti-Saccharomyces cerevisiae antibodies (gASCA). RESULTS: gASCA antibodies showed the highest sensitivity (67%) for a CD diagnosis, followed by AMCA (31%), ACCA (27%), and ALCA (25%). Positivity of at least one of the four assays increased the overall sensitivity of antibody testing in CD up to 85.5%. Mean serum gASCA levels were significantly higher in CD patients who were younger at diagnosis and had a longer disease duration before blood sampling (P<0.001). In nonstricturing, nonpenetrating CD, serum gASCA levels were lower than in patients with stricturing and/or penetrating behavior (P<0.05). The strongest association of gASCA was found with ileocolonic CD and with upper gastrointestinal disease (P<0.001). No association between anticarbohydrate (AMCA, ACCA, and ALCA) antibodies and CD location, behavior, age at onset, and disease duration was found; however, that sample size of some of our subgroups was probably too small to make firm conclusions on associations with all CD phenotypes. None of the assessed anticarbohydrate assays was predictive of colonic CD in patients in whom the distinction between CD and ulcerative colitis is not obvious using routine diagnostic methods. There was no relationship between the presence or concentration of anticarbohydrate antibodies and the inflammation measured by C-reactive protein levels. CONCLUSION: The use of a panel of anticarbohydrate antibodies may provide additional help in distinguishing IBD from non-IBD disease patterns. The addition of AMCA, ALCA, and ACCA assays as IBD serology markers improves the overall sensitivity of immunological examinations in IBD; however, anticarbohydrate assays are not helpful for predicting CD behavior.

• Exogenous alkaline phosphatase for the treatment of patients with moderate to severe ulcerative colitis.

  Authors: Milan Lukas, Pavel Drastich, Michal Konecny, Paolo Gionchetti, Ondrej Urban, Franco Cantoni, Martin Bortlik, Dana Duricova, Michael Bulitta

  Inflammatory bowel diseases. 11/2009;

  BACKGROUND:: Increased activity of intestinal alkaline phosphatase (AP) occurs locally in patients with ulcerative colitis (UC), aimed at repairing inflammatory tissue damage. We evaluated the safetyBACKGROUND:: Increased activity of intestinal alkaline phosphatase (AP) occurs locally in patients with ulcerative colitis (UC), aimed at repairing inflammatory tissue damage. We evaluated the safety and preliminary efficacy of exogenous AP administered to patients with UC in an open-label, first-in-patient exploratory trial, conducted in the Internal Medicine and Gastroenterology hospital departments in the Czech Republic and Italy. METHODS:: Twenty-one patients were enrolled (13 females), age 23-54 years, with steroid- and/or immunosuppressant-refractory, moderate/severe UC (Mayo score 6-11). Oral AP enzyme 30,000 U was administered daily for 7 days, intraduodenally. Efficacy outcomes were changes in Mayo score at Day 21 posttreatment; changes in Modified Truelove-Witts Severity index (MTWSI) at Days 21, 63; C-reactive protein and stool calprotectin levels at Days 7, 21, 63. Safety evaluations were adverse events and laboratory abnormalities reported up to Day 63 posttreatment. RESULTS:: No clinically relevant adverse events causing withdrawal or considered serious, or laboratory abnormalities or antibody formation against AP were observed. Mayo scores were significantly decreased at Day 21, and MTWSI at Days 21 and 63. C-reactive protein and stool calprotectin levels were decreased at Days 21 and 63. Clinical response on the Mayo score after a single 7-day AP course was 48% at Day 21. CONCLUSIONS:: In this uncontrolled trial, administration of exogenous AP enzyme daily over a 7-day course to patients with UC was associated with short-term improvement in disease activity scores, with clinical effects being observed within 21 days and associated with reductions in C-reactive protein and stool calprotectin. AP enzyme treatment was well tolerated and nonimmunogenic. (Inflamm Bowel Dis 2009;).

• Delayed-Release Oral Mesalamine 4.8 g/day (800mg tablet) is Effective for Patients with Moderately Active Ulcerative Colitis.

  Authors: William J Sandborn, Jaroslaw Regula, Brian G Feagan, Elena Belousova, Njegica Jojic, Milan Lukas, Bruce Yacyshyn, Piotr Krzeski, Chyon-Hwa Yeh, Christi A Messer, Stephen B Hanauer

  Gastroenterology. 09/2009;

  BACKGROUND AND AIMS:: It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted toBACKGROUND AND AIMS:: It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC. METHODS:: A multi-center, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the non-inferiority of delayed-release mesalamine 4.8 g/day (Asacol(R) HD, 800mg tablet) with 2.4 g/day (Asacol(R), 400mg tablet) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at Week 6, defined as improvement in the Physician's Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment. RESULTS:: The primary objective of non-inferiority was met. Seventy percent (273/389) of patients that received 4.8 g/day of mesalamine achieved treatment success at Week 6, compared with 66% (251/383) of patients receiving 2.4 g/day (95% Confidence Interval for 2.4 g/day minus 4.8 g/day: -11.2, 1.9). In addition, 43% of patients that received 4.8 g/day mesalamine achieved clinical remission at Week 6 compared with 35% of patients that received 2.4 g/day (p=0.04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well tolerated with similar adverse events. CONCLUSIONS:: Delayed-release mesalamine 4.8 g/day (800 mg tablet) is efficacious and well tolerated in patients with moderately active UC.

• Association of IL23R p.381Gln and ATG16L1 p.197Ala With Crohn Disease in the Czech Population.

  Authors: Petra Dusatkova, Ondrej Hradsky, Martin Lenicek, Jiri Bronsky, Jiri Nevoral, Radana Kotalova, Katerina Bajerova, Libor Vitek, Milan Lukas, Ondrej Cinek

  Journal of pediatric gastroenterology and nutrition. 08/2009;

  OBJECTIVES:: An association of variants in the genes encoding the interleukin 23 receptor (IL23R, p.Arg381Gln, rs11209026), and the autophagy-related gene 16-like 1 (ATG16L1, p.Ala197Thr, rs2241880)OBJECTIVES:: An association of variants in the genes encoding the interleukin 23 receptor (IL23R, p.Arg381Gln, rs11209026), and the autophagy-related gene 16-like 1 (ATG16L1, p.Ala197Thr, rs2241880) with Crohn disease (CD) was identified by whole genome association studies, and subsequently confirmed by other works. The aim of this study was to assess this association in the Czech population. SUBJECTS AND METHODS:: In a case-control study 333 patients with CD (137 paediatric and 196 adult-onset) and 499 unrelated healthy controls were genotyped using TaqMan SNP assays. RESULTS:: The IL23R p.381Gln allele was protective against CD in the Czech population (allelic frequency 3.2% in patients vs 5.5% in control subjects; OR 0.56, 95% CI 0.33-0.93, P = 0.02). ATG16L1 p.197Ala allele conferred increased risk of CD (allelic frequency 60% in patients vs 51% in controls; OR 1.25, 95% CI 1.02-1.52, P = 0.03). There was no appreciable difference in the effect of the associated alleles across the strata of CARD15-conferred risk. The IL23R and ATG16L1 variants did not influence the age at diagnosis, and in the genotype-phenotype analysis, the only detected association was a weak one between IL23R p.381Gln and involvement of the upper gastrointestinal tract (uncorrected P = 0.031). CONCLUSIONS:: We confirmed the role of IL23R and ATG16L1 in the CD susceptibility in the Czech population, and found a weak protective effect of IL23R p.381Gln against upper gastrointestinal tract involvement.

• What is the time for surgery in severe Crohn's disease?

  Authors: Milan Lukas

  Inflammatory bowel diseases. 10/2008; 14(S2):S271-S272.

• CYP7A1 promoter polymorphism -203A>C affects bile salt synthesis rate in patients after ileal resection.

  Authors: Martin Lenicek, Viktor Komarek, Miluse Zimolova, Jan Kovar, Milan Jirsa, Milan Lukas, Libor Vitek

  Journal of lipid research. 08/2008;

  Cholesterol 7alpha-hydroxylase (CYP7A1) plays a crucial role in cholesterol metabolism and has been implicated in genetic susceptibility to atherosclerosis. Thus, an understanding of itsCholesterol 7alpha-hydroxylase (CYP7A1) plays a crucial role in cholesterol metabolism and has been implicated in genetic susceptibility to atherosclerosis. Thus, an understanding of its transcriptional regulation is of considerable importance. We evaluated the effect of a common -203A>C polymorphism in the CYP7A1 promoter region on the activity of CYP7A1, estimated as the ratios of serum 7alpha-hydroxycholest-4-en-3-one (C4) to either total or non-HDL cholesterol. The study was performed on patients after resection of the distal ileum, leading to upregulation of CYP7A1 activity (n=65): healthy volunteers served as the control group (n=66). Whereas higher CYP7A1 activity was associated with the -203A allele in the patient group (C4/cholesterol ratio: 29.0 vs. 14.8 mug/mmol, p=0.032; C4/non-HDL cholesterol ratio: 53.3 vs. 21.3 mug/mmol in -203AA and -203CC, p=0.017, respectively): no differences were observed in the healthy controls. We conclude that under physiological conditions, the -203A>C polymorphism in the CYP7A1 gene promoter region does not seem to have any clinically relevant effect. However, in patients with severe bile salt (BS) malabsorption this polymorphism markedly affects CYP7A1 activity.

• Improved HPLC analysis of serum 7alpha-hydroxycholest-4-en-3-one, a marker of bile acid malabsorption.

  Authors: Martin Lenicek, Miroslava Juklova, Jaroslav Zelenka, Jan Kovar, Milan Lukas, Martin Bortlik, Libor Vitek

  Clinical chemistry. 07/2008; 54(6):1087-8.

• Polymorphisms of the TPMT Gene in the Czech Healthy Population and Patients with Inflammatory Bowel Disease.

  Authors: Ondrej Slanar, Martin Bortlik, Helena Buzkova, Robert Donoval, Kristina Pechandova, Ivan Sebesta, Milan Lukas, Frantisek Perlik

  Nucleosides, nucleotides & nucleic acids. 07/2008; 27(6):835-8.

  Genetic variation in thiopurine S-methyltransferase (TPMT) is a major factors for wide variation in the metabolism and safety of thiopurine drugs. We investigated the frequency of functional geneGenetic variation in thiopurine S-methyltransferase (TPMT) is a major factors for wide variation in the metabolism and safety of thiopurine drugs. We investigated the frequency of functional gene polymorphisms in 396 patients with inflammatory bowel disease and 300 healthy subjects. Frequencies of functionally deficient alleles TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3B in the patient group were 0.1%, 4.3%, 0.1%, and 0.4%, respectively, and were similar to those of healthy subjects in the Czech population. Our results provide necessary information for pharmacoeconomic studies in the Czech Republic.

• IBD patients need in health quality of care ECCO consensus.

  Authors: Margarita Elkjaer, Gabrielle Moser, Walter Reinisch, Dana Durovicova, Milan Lukas, Boris Vucelic, Vibeke Wewer, Jean Frederic Colombel, Mary Shuhaibar, Colm O'Morain, Patrizia Politi, Selwyn Odes, Tomm Bernklev, Tom Oresland, Inna Nikulina, Elena Belousova, Ingrid Van der Eijk, Pia Munkholm

  Journal of Crohn's & colitis. 06/2008; 2(2):181-8.

  : Inflammatory bowel diseases (IBD) is a lifelong disorder with increasing incidence and prevalence. IBD primarily affects young people's productivity in addition to direct and indirect costs. The: Inflammatory bowel diseases (IBD) is a lifelong disorder with increasing incidence and prevalence. IBD primarily affects young people's productivity in addition to direct and indirect costs. The chronic nature of the disease and the patients' requirement of frequent and easy access to the Health Care providers regarding lifelong medication, social and psychological support and regular follow-up in out-patient clinics are important considerations to address. : To define IBD patient needs in Quality of Health Care (QoHC) in Europe based on up- to date available evidence. The working group consisted of doctors, nurses and patient organizations from 12 European countries and Israel. Pub Med searching was performed as defined in the Delta Method. Each recommendation was graded (RG) in accordance with level of evidence (EL) based on Evidence Based Medicine, Oxford Centre. During UEGW 2007 the group reconvened to agree on the final version for each chapter of guideline statement : Pub Med search led to 6 RCT, 7 reviews, 63 original articles, but no meta-analysis regarding "Information"; "Education"; "Primary Care", "Quality of life", "Psychological help" and "Benchmarking of Health Care systems" in IBD. Seven ECCO statements have been worked out. : Evidence-based medicine in QoHC is limited. It is concluded that optimizing QoHC by "information"; "education", "benchmarking" and "psychological analysis" helps the patient to understand the disease and comply with its therapy, increasing QoL, reducing depression and anxiety. Future aspects regarding more evidence-based science and optimization of QoHC in IBD throughout Europe have been proposed.