Maria Papp

Publications of Maria Papp

• Acute phase proteins in the diagnosis and prediction of cirrhosis associated bacterial infections.

  Authors: Maria Papp, Zsuzsanna Vitalis, Istvan Altorjay, Istvan Tornai, Miklos Udvardy, Jolan Harsfalvi, Andras Vida, Janos Kappelmayer, Peter L Lakatos, Peter Antal-Szalmas

  Liver international : official journal of the International Association for the Study of the Liver. 12/2011;

  BACKGROUND: Bacterial infections are common cause of morbidity and mortality in patients with cirrhosis. The early diagnosis of these infections is rather difficult. AIMS: To assess the accuracy ofBACKGROUND: Bacterial infections are common cause of morbidity and mortality in patients with cirrhosis. The early diagnosis of these infections is rather difficult. AIMS: To assess the accuracy of acute phase proteins in the identification of bacterial infections. METHODS: Concentration of C-reactive protein (CRP), procalcitonin (PCT), lipopolysaccharide-binding protein (LBP), sCD14 and antimicrobial antibodies were measured in serum of 368 well-characterized patients with cirrhosis of whom 139 had documented infection. Clinical data was gathered by reviewing the patients' medical charts. RESULTS: Serum levels of CRP, PCT and LBP were significantly higher in patients with clinically overt infections. Among the markers, CRP - using a 10 mg/L cut-off value- proved to be the most accurate in identifying patients with infection (AUC: 0.93). The accuracy of CRP, however, decreased in advanced stage of the disease, most probably because of the significantly elevated CRP levels in non-infected patients. Combination of CRP and PCT increased the sensitivity and negative predictive value, compared with CRP on its own, by 10 and 5% respectively. During a 3-month follow-up period in patients without overt infections, Kaplan-Meier and proportional Cox-regression analyses showed that a CRP value of >10 mg/L (P = 0.035) was independently associated with a shorter duration to progress to clinically significant bacterial infections. There was no correlation between acute phase protein levels and antimicrobial seroreactivity. CONCLUSIONS: C-reactive protein on its own is a sensitive screening test for the presence of bacterial infections in cirrhosis and is also a useful marker to predict the likelihood of clinically significant bacterial infections in patients without overt infections.

• High-sensitivity C-reactive protein for identification of disease phenotype, active disease, and clinical relapses in Crohn's disease: A marker for patient classification?

  Authors: Lajos Sandor Kiss, Maria Papp, Barbara Dorottya Lovasz, Zsuzsanna Vegh, Petra Anna Golovics, Eszter Janka, Eva Varga, Miklos Szathmari, Peter Laszlo Lakatos

  Inflammatory bowel diseases. 11/2011;

  BACKGROUND: C-reactive protein (CRP) is a traditional nonspecific marker of inflammation, with Crohn's disease (CD) being associated with a strong CRP response. Thus far, no clear cutoff values haveBACKGROUND: C-reactive protein (CRP) is a traditional nonspecific marker of inflammation, with Crohn's disease (CD) being associated with a strong CRP response. Thus far, no clear cutoff values have been determined. The authors' aim was to investigate whether high-sensitivity (hs)-CRP is useful for the identification disease phenotype, active disease, and relapse during follow-up, using a classification based on the hs-CRP value at diagnosis. METHODS: In all, 260 well-characterized, unrelated, consecutive CD patients (male/female: 120/140; duration: 7.0 ± 6.1 years), with a complete clinical follow-up, were included. Hs-CRP, clinical activity according to the Harvey-Bradshaw Index, and clinical data (disease phenotype according to the Montreal Classification, extraintestinal manifestations, smoking habits, medical therapy, and surgical events) were prospectively collected between January 1, 2008 and June 1, 2010. Medical records prior to the prospective follow-up period were analyzed retrospectively. RESULTS: In all, 32.3% of CD patients had normal hs-CRP at diagnosis. Elevated hs-CRP at diagnosis was associated with disease location (P = 0.002), noninflammatory disease behavior (P = 0.058), and a subsequent need for later azathioprine/biological therapy (P < 0.001 and P = 0.024), respectively. The accuracy of hs-CRP for identifying patients with active disease during prospective follow-up was good (area under the curve [AUC]: 0.82, cutoff: 10.7 mg/L). AUC was better in patients with an elevated hs-CRP at diagnosis (AUC: 0.92, cutoff: 10.3 mg/L). In Kaplan-Meier and Cox-regression analyses, hs-CRP was an independent predictor of 3- (P = 0.007) or 12-month (P = 0.001) clinical relapses for patients in remission who had elevated hs-CRP at diagnosis. In addition, perianal involvement (P = 0.01) was associated with the 12-month relapse frequency. CONCLUSIONS: Our data suggest that hs-CRP positivity at diagnosis is associated with disease location and behavior, and in patients who are hs-CRP positive at diagnosis, is an accurate marker of disease activity and a predictor of short- and medium-term clinical flare-ups during follow-up. (Inflamm Bowel Dis 2011;).

• Duodenal ulceration in a patient with celiac disease and plasminogen I deficiency: coincidence or cofactors?

  Authors: Gabor Veres, Ilma Korponay-Szabó, Erika Maka, Tibor Glasz, Petar Mamula, Maria Papp, Antal Dezsöfi, Andras Arató

  Pediatrics. 11/2011; 128(5):e1302-6.

  Celiac disease (CD) is a gluten-dependent inflammatory disease of the small bowel that affects up to 1% of the worldwide population. Despite severe mucosal abnormalities including total villousCeliac disease (CD) is a gluten-dependent inflammatory disease of the small bowel that affects up to 1% of the worldwide population. Despite severe mucosal abnormalities including total villous atrophy and autoantibody deposition, duodenal ulcer is not a feature of CD. However, a recent study found an elevated rate of peptic ulcer disease in patients with CD. Plasminogen deficiency (PLD) is an autosomal recessive disease that causes pseudomembranous lesions in different organs, but gastrointestinal involvement is rare. Here we report the case of a 6-year-old girl who had a sudden onset of hematemesis caused by duodenal ulcer. On the basis of mucosal atrophy, elevated celiac antibody levels, decreased plasminogen serum activity, and homozygous missense mutation R216H in the plasminogen gene, CD and PLD were diagnosed. This report is, to our knowledge, the first description of the 2 entities, and results of our double-immunofluorescent studies also suggest that both diseases may have a role in the ulceration process. Excessive amounts of fibrin deposition due to PLD caused the distortion of the vessels and was responsible for the unusual celiac immunoglobulin A and tissue transglutaminase 2 in vivo binding pattern. On the basis of this result, patients with CD and unknown cause of gastrointestinal ulcer may require investigation for PLD.

• Association of peroxisome proliferator-activated receptor gamma polymorphisms with inflammatory bowel disease in a Hungarian cohort.

  Authors: Szilard Poliska, Andras Penyige, Peter Laszlo Lakatos, Maria Papp, Karoly Palatka, Laszlo Lakatos, Tamas Molnar, Laszlo Nagy

  Inflammatory bowel diseases. 06/2011; 18(3):472-9.

  Inflammatory bowel disease (IBD) shows increasing incidence in the last few years in Eastern Europe, including Hungary. Since genetic susceptibility of patients plays an important role in theInflammatory bowel disease (IBD) shows increasing incidence in the last few years in Eastern Europe, including Hungary. Since genetic susceptibility of patients plays an important role in the development and pathogenesis of IBD, it is important to identify new susceptibility genes. Peroxisome proliferator-activated receptor gamma (PPARγ) is expressed in the colon and has protective effects against inflammatory processes. Our aim was to examine the association of four polymorphisms of PPARγ in a well-characterized Hungarian IBD cohort. In all, 575 Crohn's disease (CD), 103 ulcerative colitis (UC) patients, and 486 sex- and age-matched controls were examined. Four polymorphisms of PPARγ (rs10865710 [C-681G], rs2067819, rs3892175, and rs1801282 [Pro12Ala]) were genotyped by TaqMan genotyping assays. The Pro12Ala polymorphism showed significant association with CD when the frequencies of the homozygous variants (Pro/Pro vs. Ala/Ala) were compared. The minor Ala/Ala genotype was significantly less frequent in CD patients compared to the controls (odds ratio [OR] = 0.33; 95% confidence interval [CI] = 012-0.94; P = 0.03), suggesting a potential protective effect of the Ala allele. The GAGG haplotype of PPARγ confers a protective effect in CD; however, it is not significant, but in UC it has a protective effect with a significant level (OR = 0.14; 95% CI: 0.05-0.42; P = 3.78 × 10(-5) ), while GAGC increases the risk of UC (OR = 6.70; 95% CI: 3.41-13.17; P = 3.85 × 10(-10) ). In the present study we demonstrated a significant association between PPARγ polymorphisms and the development of CD and UC at single loci level and also in haplotype combinations. (Inflamm Bowel Dis 2012;).

• Serum anti-Saccharomyces cerevisiae antibodies in Greek patients with Behcet's disease.

  Authors: George Vaiopoulos, Peter Laszlo Lakatos, Maria Papp, Faedon Kaklamanis, Efrosyni Economou, Vassilis Zevgolis, John Sourdis, Kostas Konstantopoulos

  Yonsei medical journal. 03/2011; 52(2):347-50.

  We tested 59 Greek patients with Behcet's Disease (BD) for serum anti-Saccharomyces cerevisiae antibodies. No increase of these antibodies was detected in the cases compared to 55 healthy unrelatedWe tested 59 Greek patients with Behcet's Disease (BD) for serum anti-Saccharomyces cerevisiae antibodies. No increase of these antibodies was detected in the cases compared to 55 healthy unrelated blood donors from the same population. This finding is in contrast with the correlation between Saccharomyces cerevisiae antibodies and BD as reported in other populations. It seems that environmental factors may contribute to disease expression in different populations, producing different effects according to the individual's genetic predisposition. Saccharomyces cerevisiae antibodies do not seem to be of any significance in the Greek population.

• Serum lipopolysaccharide-binding protein and soluble CD14 are markers of disease activity in patients with Crohn's disease.

  Authors: Peter Laszlo Lakatos, Lajos Sandor Kiss, Karoly Palatka, Istvan Altorjay, Peter Antal-Szalmas, Eszter Palyu, Miklos Udvardy, Tamas Molnar, Klaudia Farkas, Gabor Veres, Jolan Harsfalvi, Janos Papp, Maria Papp

  Inflammatory bowel diseases. 03/2011; 17(3):767-77.

  In inflammatory bowel disease (IBD), enhanced inflammatory activity in the gut is thought to increase the risk of bacterial translocation and endotoxemia. In the present study we investigated theIn inflammatory bowel disease (IBD), enhanced inflammatory activity in the gut is thought to increase the risk of bacterial translocation and endotoxemia. In the present study we investigated the association between serum level of lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14), and clinical disease activity, high-sensitivity C-reactive protein (hs-CRP), antimicrobial serology profile, NOD2/CARD15 status, and clinical phenotype in a large cohort of Hungarian Crohn's disease (CD) patients. In all, 214 well-characterized, unrelated, consecutive CD patients (male/female ratio: 95/119; age: 35.6 ± 13.1 years; duration:8.3 ± 7.5 years) and 110 healthy controls were investigated. Sera were assayed for LBP, sCD14, hs-CRP, ASCA IgG/IgA, anti-OMP IgA, and pANCA antibodies. NOD2/CARD15 and TLR4 variants were tested. Detailed clinical phenotypes were determined by reviewing the patients' medical charts. Serum LBP level was significantly higher (P < 0.0001 for both), while sCD14 was lower (P < 0.0001) in both active and inactive CD compared to the controls. The accuracy of hs-CRP (area under the curve [AUC] = 0.66), sCD14 (AUC = 0.70), and LBP (AUC = 0.58) was comparable for identifying patients with active disease. There was a significant correlation between LBP (P < 0.001), sCD14 (P = 0.015), and hs-CRP levels but not with antimicrobial seroreactivity or NOD2/CARD15 genotype. In inactive CD, LBP was associated with penetrating disease. In a Kaplan-Meier analysis and a proportional Cox-regression analysis, LBP (P = 0.006), sCD14 (P = 0.007), and previous relapse frequency (P = 0.023) were independently associated with time to clinical relapse during a 12-month follow-up period. Serum LBP and sCD14 are markers of disease activity in CD with a similar accuracy as hs-CRP. In addition, LBP, sCD14, and a high frequency of previous relapses were independent predictors for 1-year clinical flare-up. (Inflamm Bowel Dis 2011).

• Serologic antiglycan antibodies in inflammatory bowel disease.

  Authors: Peter Laszlo Lakatos, Maria Papp, Florian Rieder

  The American journal of gastroenterology. 01/2011; 106(3):406-12.

  At diagnosis, the clinical presentation of both entities of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), can be highly heterogeneous, leading to a delay inAt diagnosis, the clinical presentation of both entities of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), can be highly heterogeneous, leading to a delay in correct identification or differentiation between CD and UC in a subgroup of patients. In addition, the natural history of IBD patients is strikingly variable. During the life of a CD patient, in the majority of instances, stricturing or perforating complications occur, leading to surgery. Serologic antiglycan antibodies directed against various microbial carbohydrate epitopes are useful in differentiation of CD vs. UC and are a promising tool for identification of CD patients at risk for rapid progression and need for surgical intervention. Instruments for prediction of CD behavior are critical, as the use of immunomodulators and/or biologicals early in the disease course might be justified for patients with a high hazard for complicated disease behavior.

• Phenotypic polymorphism of haptoglobin: a novel risk factor for the development of infection in liver cirrhosis.

  Authors: Zsuzsanna Vitalis, Istvan Altorjay, Istvan Tornai, Karoly Palatka, Sandor Kacska, Eszter Palyu, David Tornai, Miklos Udvardy, Jolan Harsfalvi, Tamas Dinya, Gabor Veres, Peter Laszlo Lakatos, Maria Papp

  Human immunology. 01/2011; 72(4):348-54.

  The α-chain alleles 1 and 2 of haptoglobin (Hp) molecule account for three phenotypes, which have biologically important differences in their antioxidant, scavenging, and immunomodulatory propertiesThe α-chain alleles 1 and 2 of haptoglobin (Hp) molecule account for three phenotypes, which have biologically important differences in their antioxidant, scavenging, and immunomodulatory properties and may thereby influence the course of inflammatory diseases. A follow-up observational study was conducted to assess the association between haptoglobin phenotype and the development of clinically significant bacterial infections in patients with liver cirrhosis. Sera of 336 patients with liver cirrhosis of various etiologies and 384 healthy subjects were investigated. Haptoglobin phenotypes were determined by gel electrophoresis and assigned corresponding genotype. Haptoglobin phenotype distributions of patients and controls was similar (Hp1-1: 10.7% vs 11.5%, Hp2-1: 47.9% vs 46.1% and Hp2-2: 41.4% vs 42.4%). The probability of clinically significant bacterial infections was calculated for each haptoglobin phenotype (Hp1-1: 50.0%, Hp2-1: 36.0% and Hp2-2: 26.6%, p = 0.039). In a logistic regression analysis, Hp1-1 phenotype (p = 0.015, OR: 2.74, 95% CI: 1.22-6.13), Child-Pugh stage (p = 0.038, OR: 1.40, 95% CI: 1.02-1.91) and presence of co-morbidities (p < 0.001, OR: 2.64, 95% CI: 1.63-4.27) were independently associated with infections. In a Cox regression analysis, Hp1-1 phenotype (p = 0.014), Child-Pugh stage C (p < 0.001), and presence of co-morbidities (p = 0.004) were associated with time to first infectious episode. Phenotypic haptoglobin polymorphism was independent predictor for risk and time to first clinically significant bacterial infectious episode.

• 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.

• Association of adherence to therapy and complementary and alternative medicine use with demographic factors and disease phenotype in patients with inflammatory bowel disease.

  Authors: Peter Laszlo Lakatos, Zsofia Czegledi, Gyula David, Zsofia Kispal, Lajos S Kiss, Karoly Palatka, Tunde Kristof, Ferenc Nagy, Agnes Salamon, Pal Demeter, Pal Miheller, Tamas Szamosi, Janos Banai, Maria Papp, Laszlo Bene, Agota Kovacs, Istvan Racz, Laszlo Lakatos

  Journal of Crohn's & colitis. 09/2010; 4(3):283-90.

  Previous studies have suggested an increasing use of complementary and alternative medicine (CAM) in patients with inflammatory bowel disease (IBD). Furthermore, a significant number of IBD patientsPrevious studies have suggested an increasing use of complementary and alternative medicine (CAM) in patients with inflammatory bowel disease (IBD). Furthermore, a significant number of IBD patients fail to comply with treatment. The aim of our study was to evaluate the prevalence of non-adherence and the use of CAM in Hungarian patients with IBD. A total of 655 consecutive IBD patients (CD: 344, age: 38.2 [SD 12.9]years; UC: 311, age: 44.9 [15.3]years) were interviewed during the specialist visit by self-administered questionnaire including demographic and disease-related data as well as items analyzing the extent of non-adherence and CAM use. Patients taking more than 80% of each prescribed medication were classified as adherent. The overall rate of self-reported non-adherence (CD: 20.9%, UC: 20.6%) and CAM (CD: 31.7%, UC: 30.9%) use did not differ between Crohn's disease (CD) and ulcerative colitis (UC). The most common causes of non-adherence were: forgetfulness (47.8%), too many/unnecessary pills (39.7%), being afraid of side effects (27.9%) and too frequent dosing. Most common forms of CAM were herbal tea (47.3%), homeopathy (14.6%), special diet (12.2%), and acupuncture (5.8%). In CD, disease duration, date of last follow-up visit, educational level and previous surgeries were predicting factors for non-adherence. Alternative medicine use was associated in both diseases with younger age, higher educational level, and immunosuppressant use. In addition, CAM use in UC was more common in females and in patients with supportive psychiatric/psychological therapy. Non-adherence and CAM use is common in patients with IBD. Special attention should be paid to explore the identified predictive factors during follow-up visits to improve adherence to therapy and improving patient-doctor relationship.

• Mannose-binding lectin deficiency confers risk for bacterial infections in a large Hungarian cohort of patients with liver cirrhosis.

  Authors: Istvan Altorjay, Zsuzsanna Vitalis, Istvan Tornai, Karoly Palatka, Sandor Kacska, Gyula Farkas, Miklos Udvardy, Jolan Harsfalvi, Tamas Dinya, Peter Orosz, Bela Lombay, Gabriella Par, Alajos Par, Timea Csak, Janos Osztovits, Ferenc Szalay, Antal Csepregi, Peter Laszlo Lakatos, Maria Papp

  Journal of hepatology. 09/2010; 53(3):484-91.

  Mannose-binding lectin (MBL) is a serum lectin synthesized by the liver and involved in innate host defense. MBL deficiency increases the risk of various infectious diseases mostly inMannose-binding lectin (MBL) is a serum lectin synthesized by the liver and involved in innate host defense. MBL deficiency increases the risk of various infectious diseases mostly in immune-deficient conditions. Bacterial infections are a significant cause of morbidity and mortality in liver cirrhosis due to the relative immuncompromised state. Sera of 929 patients with various chronic liver diseases [autoimmune liver diseases (ALD), 406; viral hepatitis C (HCV), 185; and liver cirrhosis (LC) with various etiologies, 338] and 296 healthy controls (HC) were assayed for MBL concentration. Furthermore, a follow-up, observational study was conducted to assess MBL level as a risk factor for clinically significant bacterial infections in cirrhotic patients. MBL level and the prevalence of absolute MBL deficiency (<100 ng/ml) was not significantly different between patients and controls (ALD: 14.5%, HCV: 11.9%, LC: 10.7%, HC: 15.6%). In cirrhotic patients, the risk for infection was significantly higher among MBL deficient subjects as compared to non-deficient ones (50.0% vs. 31.8%, p=0.039). In a logistic regression analysis, MBL deficiency was an independent risk factor for infections (OR: 2.14 95% CI: 1.03-4.45, p=0.04) after adjusting for Child-Pugh score, co-morbidities, gender, and age. In a Kaplan-Meier analysis, MBL deficiency was associated with a shorter time to develop the first infectious complication (median days: 579 vs. 944, pBreslow=0.016, pLogRank=0.027) and was identified as an independent predictor in a multivariate Cox-regression analysis (p=0.003, OR: 2.33, 95% CI: 1.34-4.03). MBL deficiency is associated with a higher probability and shorter time of developing infections in liver cirrhosis, further supporting the impact of the MBL molecule on the host defense.

• Mannose-binding lectin level and deficiency is not associated with inflammatory bowel diseases, disease phenotype, serology profile, and NOD2/CARD15 genotype in a large Hungarian cohort.

  Authors: Maria Papp, Peter Laszlo Lakatos, Jolan Harsfalvi, Gyula Farkas, Karoly Palatka, Miklos Udvardy, Tamas Molnar, Klaudia Farkas, Ferenc Nagy, Gabor Veres, Laszlo Lakatos, Agota Kovacs, Tamas Dinya, Agnes Katalin Kocsis, Janos Papp, Istvan Altorjay

  Human immunology. 04/2010; 71(4):407-13.

  Mannose-binding lectin (MBL) is a major, soluble, pattern-recognition molecule and an important component of the innate host defense. The role of MBL in inflammatory bowel diseases (IBDs) isMannose-binding lectin (MBL) is a major, soluble, pattern-recognition molecule and an important component of the innate host defense. The role of MBL in inflammatory bowel diseases (IBDs) is controversial. We determined the prevalence of MBL deficiency in a Hungarian IBD patients' cohort, and whether it is associated with the antimicrobial antibody formation or particular clinical manifestations. Nine hundred ninety IBD patients and 225 healthy subjects were investigated. Sera were assayed for MBL and a panel of antimicrobial antibodies (anti-OMP, anti-Saccharomyces cerevisiae antibodies, and antiglycans) by ELISA. TLR4 and NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism. Median MBL level was not significantly different between IBDs (Crohn's disease [CD]: 929; ulcerative colitis [UC]: 810 ng/ml) and the control group (1027 ng/ml), as well as the prevalence of absolute MBL deficiency (<100 ng/ml) (CD: 15.0%, UC: 18.4%, controls: 15.6%). The presence of a low MBL level (<500 ng/ml) was not associated with any of the examined serologic markers, or their combinations. In addition, there was no association with the clinical presentation, disease course, or response to treatment. TLR4 variant genotype was more common in CD patients without MBL deficiency (11% vs. 1.7%, OR: 7.29, 95% CI: 1.08-53.9, p = 0.02). We failed to confirm any association between MBL deficiency and serologic marker positivity. MBL deficiency was not predictive for clinical phenotype or disease activity in IBDs.

• Presence of anti-microbial antibodies in liver cirrhosis--a tell-tale sign of compromised immunity?

  Authors: Maria Papp, Gary L Norman, Zsuzsanna Vitalis, Istvan Tornai, Istvan Altorjay, Ildiko Foldi, Miklos Udvardy, Zakera Shums, Tamas Dinya, Peter Orosz, Bela Lombay, Gabriella Par, Alajos Par, Gabor Veres, Timea Csak, Janos Osztovits, Ferenc Szalay, Peter Laszlo Lakatos

  PloS one. 01/2010; 5(9):e12957.

  Bacterial translocation plays important role in the complications of liver cirrhosis. Antibody formation against various microbial antigens is common in Crohn's disease and considered to be caused byBacterial translocation plays important role in the complications of liver cirrhosis. Antibody formation against various microbial antigens is common in Crohn's disease and considered to be caused by sustained exposure to gut microflora constituents. We hypothesized that anti-microbial antibodies are present in patients with liver cirrhosis and may be associated with the development of bacterial infections. Sera of 676 patients with various chronic liver diseases (autoimmune diseases: 266, viral hepatitis C: 124, and liver cirrhosis of different etiology: 286) and 100 controls were assayed for antibodies to Saccharomyces cerevisiae (ASCA) and to antigens derived from two intestinal bacterial isolates (one gram positive, one gram negative, neither is Escherichia coli). In patients with liver cirrhosis, we also prospectively recorded the development of severe episodes of bacterial infection. ASCA and anti-OMP Plus™ antibodies were present in 38.5% and 62.6% of patients with cirrhosis and in 16% and 20% of controls, respectively (p<0.001). Occurrence of these antibodies was more frequent in cases of advanced cirrhosis (according to Child-Pugh and MELD score; p<0.001) or in the presence of ascites (p<0.001). During the median follow-up of 425 days, 81 patients (28.3%) presented with severe bacterial infections. Anti-microbial antibody titers (p = 0.003), as well as multiple seroreactivity (p = 0.036), was associated with infectious events. In logistic regression analysis, the presence of ascites (OR: 1.62, 95%CI: 1.16-2.25), co-morbidities (OR: 2.22, 95%CI: 1.27-3.86), and ASCA positivity (OR: 1.59, 95%CI: 1.07-2.36) were independent risk factors for severe infections. A shorter time period until the first infection was associated with the presence of ASCA (p = 0.03) and multiple seropositivity (p = 0.037) by Kaplan-Meier analysis, and with Child-Pugh stage (p = 0.018, OR: 1.85) and co-morbidities (p<0.001, OR: 2.02) by Cox-regression analysis. The present study suggests that systemic reactivity to microbial components reflects compromised mucosal immunity in patients with liver cirrhosis, further supporting the possible role of bacterial translocation in the formation of anti-microbial antibodies.

• Peripheral blood gene expression patterns discriminate among chronic inflammatory diseases and healthy controls and identify novel targets.

  Authors: Bertalan Mesko, Szilard Poliska, Andrea Szegedi, Zoltan Szekanecz, Karoly Palatka, Maria Papp, Laszlo Nagy

  BMC medical genomics. 01/2010; 3:15.

  Chronic inflammatory diseases including inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), psoriasis and rheumatoid arthritis (RA) afflict millions of people worldwide, butChronic inflammatory diseases including inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), psoriasis and rheumatoid arthritis (RA) afflict millions of people worldwide, but their pathogenesis is still not well understood. It is also not well known if distinct changes in gene expression characterize these diseases and if these patterns can discriminate between diseased and control patients and/or stratify the disease. The main focus of our work was the identification of novel markers that overlap among the 3 diseases or discriminate them from each other. Diseased (n = 13, n = 15 and n = 12 in IBD, psoriasis and RA respectively) and healthy patients (n = 18) were recruited based on strict inclusion and exclusion criteria; peripheral blood samples were collected by clinicians (30 ml) in Venous Blood Vacuum Collection Tubes containing EDTA and peripheral blood mononuclear cells were separated by Ficoll gradient centrifugation. RNA was extracted using Trizol reagent. Gene expression data was obtained using TaqMan Low Density Array (TLDA) containing 96 genes that were selected by an algorithm and the statistical analyses were performed in Prism by using non-parametric Mann-Whitney U test (P-values < 0.05). Here we show that using a panel of 96 disease associated genes and measuring mRNA expression levels in peripheral blood derived mononuclear cells; we could identify disease-specific gene panels that separate each disease from healthy controls. In addition, a panel of five genes such as ADM, AQP9, CXCL2, IL10 and NAMPT discriminates between all samples from patients with chronic inflammation and healthy controls. We also found genes that stratify the diseases and separate different subtypes or different states of prognosis in each condition. These findings and the identification of five universal markers of chronic inflammation suggest that these diseases have a common background in pathomechanism, but still can be separated by peripheral blood gene expression. Importantly, the identified genes can be associated with overlapping biological processes including changed inflammatory response. Gene panels based on such markers can play a major role in the development of personalized medicine, in monitoring disease progression and can lead to the identification of new potential drug targets in chronic inflammation.

• Anti-microbial antibodies in celiac disease: trick or treat?

  Authors: Maria Papp, Ildiko Foldi, Istvan Altorjay, Eszter Palyu, Miklos Udvardy, Judit Tumpek, Sandor Sipka, Ilma Rita Korponay-Szabo, Eva Nemes, Gabor Veres, Tamas Dinya, Attila Tordai, Hajnalka Andrikovics, Gary L Norman, Peter Laszlo Lakatos

  World journal of gastroenterology : WJG. 09/2009; 15(31):3891-900.

  AIM: To determine the prevalence of a new set of anti-glycan and anti-outer membrane protein (anti-OMP) antibodies in a Hungarian cohort of adult Celiac disease (CD) patients. METHODS: 190AIM: To determine the prevalence of a new set of anti-glycan and anti-outer membrane protein (anti-OMP) antibodies in a Hungarian cohort of adult Celiac disease (CD) patients. METHODS: 190 consecutive CD patients [M/F: 71/119, age:39.9 (SD:14.1) years], 100 healthy, and 48 gastrointestinal controls were tested for glycan anti-Saccharomyces cerevisiae (gASCA), anti-laminaribioside (ALCA), anti-chitobioside, anti-mannobioside, anti-OMP antibodies and major NOD2/CARD15 mutations. Thirty out of 82 CD patients enrolled at the time of diagnosis were re-evaluated for the same antibodies after longstanding gluten-free diet (GFD). RESULTS: 65.9% of the CD patients were positive for at least one of the tested antibodies at the time of the diagnosis. Except anti-OMP and ALCA, anti-microbial antibodies were exclusively seen in untreated CD; however, the overall sensitivity was low. Any glycan positivity (LR+: 3.13; 95% CI: 2.08-4.73) was associated with an increased likelihood ratio for diagnosing CD. Significant correlation was found between the levels of anti-glycan and anti-endomysial or anti-transglutaminase antibodies. Anti-glycan positivity was lost after longstanding GFD. Anti-glycan antibody titers were associated with symptoms at presentation, but not the presence of NOD2/CARD15 mutations. Patients with severe malabsorption more frequently had multiple antibodies at diagnosis (P = 0.019). CONCLUSION: The presence of anti-glycan antibodies in CD seems to be secondary to the impaired small bowel mucosa which can lead to increased antigen presentation. Furthermore, anti-glycan positivity may be considered an additional marker of CD and dietary adherence.

• Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe - a Hungarian nationwide observational study.

  Authors: Pal Miheller, Peter Lakatos, Gabor Horvath, Tamas Molnar, Tamas Szamosi, Zsofia Cegledi, Agnes Salamon, Jozsef Czimmer, Gyorgy Rumi, Karoly Palatka [......] Bela Hunyady, Laszlo Simon, Janos Papp, Janos Banai, Ferenc Nagy, Janos Lonovits, Laszlo Ujszaszy, Gyorgyi Muzes, Laszlo Herszenyi, Zsolt Tulassay

  BMC gastroenterology. 09/2009; 9(1):66.

  ABSTRACT: BACKGROUND: Infliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohn's disease (CD), with efficacy in theABSTRACT: BACKGROUND: Infliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohn's disease (CD), with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary. METHODS: During a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5mg/kg IFX infusions given at week 0, 2 and 6) at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy. RESULTS: Three hundred and sixty three patients (183 women and 180 men) were treated with IFX since 2000. Mean age was 33.5 +/- 11.2 years and the mean duration of disease was 6.7 +/- 6.1 years. The population included 114 patients (31.4%) with therapy-refractory CD, 195 patients (53.7%) with fistulas, 16 patients (4.4%) with both therapy-refractory CD and fistulas, and 26 patients (7.2%) with steroid dependent CD. Five patients (1.4%) were treated with metastatic CD and 7 patients (1.9%) with other CD related indications. A full course of IFX induction therapy was successfully administered in 299 patients, and the overall response rate (CDAI decrease of 70 points) was 86.2% (313/363). A higher response rate was observed in younger patients and patients with shorter disease duration or colonic manifestations of CD. The response rate was lower in patients without concomitant immunosuppressant therapy compared to those with concomitant immunosuppressant therapy (73.0% vs. 88.2%, respectively; p<0.05). Higher response rate (closure of 50% or more of the fistulas) were observed in perianal fistulas compared to other forms. Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%), 17 delayed type hypersensitivity (4.7%), 16 infections (4.4%), and 3 malignancies (0.8%). CONCLUSIONS: IFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not influence the efficacy of IFX induction therapy.

• Early azathioprine/biological therapy is associated with decreased risk for first surgery and delays time to surgery but not reoperation in both smokers and nonsmokers with Crohn's disease, while smoking decreases the risk of colectomy in ulcerative colitis.

  Authors: Tamas Szamosi, Janos Banai, Laszlo Lakatos, Zsofia Czegledi, Gyula David, Ferenc Zsigmond, Tunde Pandur, Zsuzsanna Erdelyi, Orsolya Gemela, Maria Papp, Janos Papp, Peter Lakatos

  European journal of gastroenterology & hepatology. 08/2009;

  BACKGROUND/AIMS: Smoking may alter the natural course of Crohn's disease (CD). Smokers are more likely to develop complications, relapses and have a greater risk for surgery. In contrast, inBACKGROUND/AIMS: Smoking may alter the natural course of Crohn's disease (CD). Smokers are more likely to develop complications, relapses and have a greater risk for surgery. In contrast, in ulcerative colitis (UC), smoking might improve the disease course. Our aim was to assess the combined effect of disease phenotype, smoking, and immunomodulator [azathioprine (AZA), AZA/biological] treatment on the risk of intestinal resection/reoperation in CD and colectomy in UC. PATIENTS/METHODS: Six hundred and eighty-one inflammatory bowel disease patients were analyzed (CD: 340, male/female: 155/185, duration: 9.4+/-7.5 years; UC: 341, male/female: 174/164, duration: 11.5+/-9.7 years). Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. Medical records were retrospectively analyzed. RESULTS: Smoking was present in 45.5% in CD and 15.8% in UC. CD patients who underwent at least one bowel resection comprised 46.5%. In an univariate analysis, disease location, behavior, AZA, or AZA/biological use before surgery [odds ratio (OR): 0.26 and 0.22, P<0.001] and smoking (OR: 1.61, P = 0.03) were associated with risk for first surgery. Smoking, AZA, or AZA/biological (P<0.001) use before first surgery and disease behavior were independently associated with risk for surgery in a proportional Cox-regression analysis. Perianal disease (OR: 3.2, P = 0.001) and frequent relapses (OR: 4.8, P<0.001) but not smoking, AZA, or AZA/biological use after first surgery were predictive for reoperation. In UC, the rate of colectomy was 5.6%. Disease location (P = 0.001) and smoking status (P = 0.02) were independently associated with risk for colectomy in a proportional Cox-regression analysis. CONCLUSION: Our data suggest that early AZA/biological therapy reduces the risk for first operation but not reoperation in CD, in both smokers and nonsmokers. In contrast, smoking was associated with a decreased need for colectomy in UC.

• Evaluation of the combined application of ethanol-fixed and formaldehyde-fixed neutrophil substrates for identifying atypical P-ANCA in inflammatory bowel disease.

  Authors: Maria Papp, Istvan Altorjay, Gabriella Lakos, Judit Tumpek, Sandor Sipka, Tamas Dinya, Karoly Palatka, Gabor Veres, Miklos Udvardy, Peter Laszlo Lakatos

  Clinical and vaccine immunology : CVI. 02/2009;

  No clear guidelines for indirect immunofluorescence (IIF) detection and interpretation of antineutrophil cytoplasmic antibodies (ANCA) are proposed in inflammatory bowel diseases (IBD). We evaluatedNo clear guidelines for indirect immunofluorescence (IIF) detection and interpretation of antineutrophil cytoplasmic antibodies (ANCA) are proposed in inflammatory bowel diseases (IBD). We evaluated the reliability of combined use of ethanol- and formalin-fixed neutrophil substrates to identify atypical perinuclear (P)-ANCA under routine laboratory circumstances by indirect immunofluorescence. 204 IBD patients were assessed by four different fluorescence substrates in two distinct laboratories. Anti-myeloperoxidase (MPO) and anti-proteinase-3 (PR-3) and other specific granule proteins (elastase, lactoferrin, cathepsin G, lysozyme and bactericidal permeability-increasing protein [BPI]) were measured by ELISA. Combined application of ethanol- and formalin slides to detect atypical P-ANCA reflected lack of agreement between assays (kappa</=0.39) in the inter-assay and moderate agreement in the inter-observer study (kappa=0.42). After combining atypical and typical P-ANCA patterns together, the consensus greatly improved. 26.9% of patients were P-ANCA positive with at least 2 tests (UC: 44.3% and CD: 13.1%; p<0.0001), while overall ANCA positivity was 22.5%-34.8%. Combined application of ethanol-fixed and formaldehyde-fixed neutrophil substrates did not facilitate the differentiation between P-ANCA and atypical P-ANCA, and the results were not consistent when using substrates from different sources. Combining all P-ANCAs together ensures the highest sensitivity and specificity in differentiating UC from CD.

• Pancreatic autoantibodies are associated with reactivity to microbial antibodies, penetrating disease behavior, perianal disease, and extraintestinal manifestations, but not with NOD2/CARD15 or TLR4 genotype in a hungarian IBD cohort.

  Authors: Peter Laszlo Lakatos, Istvan Altorjay, Tamas Szamosi, Karoly Palatka, Zsuzsanna Vitalis, Judit Tumpek, Sandor Sipka, Miklos Udvardy, Tamas Dinya, Laszlo Lakatos, Agota Kovacs, Tamas Molnar, Zsolt Tulassay, Pal Miheller, Zsolt Barta, Winfried Stocker, Janos Papp, Gabor Veres, Maria Papp

  Inflammatory bowel diseases. 10/2008;

  Background: Pancreatic autoantibodies (PAB) and goblet cell autoantibodies (GAB) are specific for Crohn's disease (CD) and ulcerative colitis (UC), but the sensitivity alone is low. ConventionalBackground: Pancreatic autoantibodies (PAB) and goblet cell autoantibodies (GAB) are specific for Crohn's disease (CD) and ulcerative colitis (UC), but the sensitivity alone is low. Conventional antibodies and carbohydrates (glycans) are associated with disease phenotype and may be of diagnostic importance in inflammatory bowel disease (IBD). Our aim was to determine the accuracy of PAB and GAB autoantibodies as well as to study relevant phenotype-serotype associations.Methods: A Hungarian study cohort of 1092 subjects, including 689 well-characterized, unrelated IBD patients (CD: 579, m/f ratio: 274/305, duration: 7.9 +/- 11.2 years; UC: 110, m/f ratio: 53/57, duration: 8.9 +/- 9.8 years), 139 celiac patients, 100 healthy, and 64 non-IBD gastrointestinal controls were investigated. Sera were assayed for PAB-GAB IgA/IgG, anti-Omp, anti-Saccharomyces cerevisiae antibodies (ASCA), and anti-glycans. TLR4 and NOD2/CARD15 was tested by polymerase chain reaction / restriction fragment length polymorphism (PCR-RFLP). Detailed clinical phenotypes were determined.Results: The prevalence of PAB was significantly more frequent in CD (41.1%) versus UC (22.7%), celiac (22.3%), and controls (8% and 4.6%, P < 0.01 for each), while GAB detection was poor in all groups except UC (15.4%). In CD the combination of PAB and/or anti-glycans/ASCA increased the sensitivity to 72% and 59%, respectively, for isolated colonic disease. PAB was associated to gylcans (odds ratio [OR] 1.74,P = 0.002), ASCA IgG/IgA (OR 1.75, P = 0.002), Omp (OR 1.86, P = 0.001) as well as perforating, perianal disease, arthritis, ocular, and cutaneous manifestations (P = 0.002-0.032). In contrast, PAB and GAB antibodies were not associated with NOD2/CARD15 or TLR4, response to medical therapy, or need for surgery. No associations were found in UC.Conclusions: PAB autoantibodies in combination with ASCA or anti-glycan antibodies increase the sensitivity for detecting CD, especially isolated colonic CD. Antibody response to PAB was associated with complicated disease phenotype and extraintestinal manifestations in this Eastern European IBD cohort.(Inflamm Bowel Dis 2008).

• The 3'UTR NFKBIA Variant Is Associated with Extensive Colitis in Hungarian IBD Patients.

  Authors: Tamas Szamosi, Peter Lakatos, Aniko Szilvasi, Laszlo Lakatos, Agota Kovacs, Tamas Molnar, Istvan Altorjay, Maria Papp, Orsolya Szabo, Anna Satori, Zsolt Tulassay, Pal Miheller, Henrik Horvath, Janos Papp, Attila Tordai, Hajnalka Andrikovics

  Digestive diseases and sciences. 09/2008;

  Purpose In previous studies the NFKBIA 3'UTR (untranslated region) AA genotype was associated with Crohn's disease (CD), while the NFKB1-94ins/delATTG mutation increased the risk for ulcerativePurpose In previous studies the NFKBIA 3'UTR (untranslated region) AA genotype was associated with Crohn's disease (CD), while the NFKB1-94ins/delATTG mutation increased the risk for ulcerative colitis (UC). The aim of our study was to investigate these two polymorphisms and patients' response to medical therapy and/or disease phenotype in Hungarian inflammatory bowel disease (IBD) patients. Methods NFKBIA 3'UTR- and NFKB1-94ins/delATTG polymorphisms were investigated in 415 unrelated IBD patients (CD: 266 patients, mean age 35.2 +/- 12.1 years, duration 8.7 +/- 7.5 years; UC patients: 149, mean age 44.4 +/- 15.4 years, duration 10.7 +/- 8.9 years) and 149 controls by PCR-restriction fragment length polymorphism (RFLP) analysis. Detailed clinical phenotypes were determined by reviewing the medical charts. Results The NFKBIA 3'UTR and NFKB1-94ins/delATTG genotypes and allele frequencies were not significantly different among IBD and controls. In patients with UC, the 3'UTR GG genotype was associated with extensive colitis (55.3 vs. 29.4%, odds ratio 2.97, 95% confidence interval 1.45-6.08). The presence of variant alleles did not predict response to steroids, infliximab, or need for surgery. Conclusions The NFKBIA 3'UTR GG genotype was associated with an increased risk for extensive colitis in Hungarian patients. In contrast, variant alleles did not predict response to medical therapy or need for surgery.