Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis

AIM To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis(PSC) patients.METHODS Sera of 67 PSC patients [median age(range): 32(5-79) years, concomitant IBD: 67% and cirrhosis: 20%] were assayed for the presence of antibodies against to F-actin(AAA Ig A/Ig G) and gliadin(AGA Ig A/Ig G)] and for serum level of intestinal fatty acid-binding protein(I-FABP) by ELISA. Markers of lipopolysaccharide(LPS) exposure [LPS binding protein(LBP)] and various antimicrobial antibodies [anti-OMP Plus Ig A and endotoxin core Ig A antibody(Endo CAb)] were also determined. Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up [median: 99(14-106) mo]. One hundred and fifty-three healthy subjects(HCONT) and 172 ulcerative colitis(UC) patients were the controls. RESULTS A total of 28.4%, 28.0%, 9% and 20.9% of PSC patients were positive for AAA Ig A, AAA Ig G, AGA Ig A and AGA Ig G, respectively. Frequencies of AAA Ig A and AAA Ig G(P < 0.001, for both) and AGA Ig G(P = 0.01, for both) but not AGA Ig A were significantly higher compared to both of the HCONT and the UC groups. In survival analysis, AAA Ig A-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis [HR = 5.15(1.27-20.86), P = 0.022 or for the Mayo risk score(HR = 4.24(0.99-18.21), P = 0.052]. AAA Ig A-positivity was significantly associated with higher frequency of antimicrobial antibodies(P < 0.001 for Endo Cab Ig A and P = 0.012 for anti-OMP Plus Ig A) and higher level of the enterocyte damage marker(median I-FABP_(AAA Ig A pos vs neg): 365 vs 166 pg/m L, P = 0.011), but not with serum LBP level. CONCLUSION Presence of Ig A type AAA identified PSC patients with progressive disease. Moreover, it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage further highlighting the importance of the gut-liver interaction in PSC.

Is early limited surgery associated with a more benign disease course in Crohn's disease?

AIM:To analyze the difference in disease course and need for surgery in patients with Crohn’s disease(CD).METHODS:Data of 506 patients with incident CD were analyzed(age at diagnosis:31.5±13.8 years).Both hospital and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database,which includes incident CD patients diagnosed between January 1,1977 and December 31,2008.Follow-up data were collected until December 31,2009.All patients included had at least 1year of follow-up available.Patients with indeterminate colitis at diagnosis were excluded from the analysis.RESULTS:Overall,73 patients(14.4%)required resective surgery within 1 year of diagnosis.Steroid exposure and need for biological therapy were lower in patients with early limited surgery(P<0.001 and P=0.09).In addition,surgery rates during follow-up in patients with and without early surgery differed significantly after matching on propensity scores(P<0.001,HR=0.23).The need for reoperation was also lower in patients with early limited resective surgery(P=0.038,HR=0.42)in a Kaplan-Meier and multivariate Cox regression(P=0.04)analysis.However,this advantage was not observed after matching on propensity scores(PLogrank=0.656,PBreslow=0.498).CONCLUSION:Long-term surgery rates and overall exposure to steroids and biological agents were lower in patients with early limited resective surgery,but reoperation rates did not differ.

Prevalence, significance and predictive value of antiphospholipid antibodies in Crohn's disease

AIM: To assess the prevalence and stability of different antiphospholipid antibodies(APLAs) and their association with disease phenotype and progression in inflammatory bowel diseases(IBD) patients.METHODS: About 458 consecutive patients [Crohn's disease(CD): 271 and ulcerative colitis(UC): 187] were enrolled into a follow-up cohort study in a tertiary IBD referral center in Hungary. Detailed clinical phenotypes were determined at enrollment by reviewing the patients' medical charts. Disease activity, medical treatment and data about evolvement of complications or surgical interventions were determined prospectively during the follow-up. Disease course(development f complicated disease phenotype and need for surgery),occurrence of thrombotic events, actual state of diseaseactivity according to clinical, laboratory and endoscopic scores and accurate treatment regime were recorded during the follow-up,(median, 57.4 and 61.6 mo for CD and UC). Sera of IBD patients and 103 healthy controls(HC) were tested on individual anti-β2-Glycoprotein-I(anti-β2-GPI IgA/M/G), anti-cardiolipin(ACA IgA/M/G)and anti-phosphatidylserine/prothrombin(anti-PS/PT IgA/M/G) antibodies and also anti-Saccharomyces cerevisiae antibodies(ASCA IgA/G) by enzyme-linked immunosorbent assay(ELISA). In a subgroup of CD(n = 198) and UC patients(n = 103), obtaining consecutive samples over various arbitrary timepoints during the disease course, we evaluated the intraindividual stability of the APLA status. Additionally,we provide an overview of studies, performed so far, in which significance of APLAs in IBD were assessed.RESULTS: Patients with CD had significantly higher prevalence of both ACA(23.4%) and anti-PS/PT(20.4%) antibodies than UC(4.8%, p < 0.0001 and10.2%, p = 0.004) and HC(2.9%, p < 0.0001 and15.5%, p = NS). No difference was found for the prevalence of anti-β2-GPI between different groups(7.2%-9.7%). In CD, no association was found between APLA and ASCA status of the patients.Occurrence of anti-β2-GPI, ACA and anti-PS/PT was not different between the group of patients with active vs inactive disease state according to appropriate clinical, laboratory and endoscopic scores in CD as well as in UC patients. All subtypes of anti-β2-GPI and ACA IgM status were found to be very stable over time, in contrast ACA IgG and even more ACA IgA status showed significant intraindividual changes.Changes in antibody status were more remarkable in CD than UC(ACA IgA: 49.9% vs 23.3% and ACA IgG:21.2% vs 5.8%). Interestingly, 59.1% and 30.1% of CD patients who received anti-TNF therapy showed significant negative to positive changes in ACA IgA and IgG antibody status respectively. APLA status was not associated with the clinical phenotype at diagnosis or during follow-up, medical therapy, or thrombotic events and it was not associated with the probability of developing complicated disease phenotype or surgery in a Kaplan-Meier analysis.CONCLUSION: The present study demonstrated enhanced formation of APLAs in CD patients. However,presence of different APLAs were not associated with the clinical phenotype or disease course.

Immune phenotype in children with therapy-nave remitted and relapsed Crohn’s disease

AIM: To characterize the prevalence of subpopulations of CD4+ cells along with that of major inhibitor or stimulator cell types in therapy-nave childhood Crohn's disease (CD) and to test whether abnormalities of immune phenotype are normalized with the improvement of clinical signs and symptoms of disease. METHODS: We enrolled 26 pediatric patients with CD. 14 therapy-nave CD children; of those, 10 children remitted on conventional therapy and formed the remission group. We also tested another group of 12 chil-dren who relapsed with conventional therapy and were given infliximab; and 15 healthy children who served as controls. The prevalence of Th1 and Th2, nave and memory, activated and regulatory T cells, along with the members of innate immunity such as natural killer (NK), NK-T, myeloid and plasmocytoid dendritic cells (DCs), monocytes and Toll-like receptor (TLR)-2 and TLR-4 expression were determined in peripheral blood samples. RESULTS: Children with therapy-nave CD and those in relapse showed a decrease in Th1 cell prevalence. Simultaneously, an increased prevalence of memory and activated lymphocytes along with that of DCs and monocytes was observed. In addition, the ratio of myeloid /plasmocytoid DCs and the prevalence of TLR-2 or TLR-4 positive DCs and monocytes were also higher in therapy-nave CD than in controls. The majority of alterations diminished in remitted CD irrespective of whether remission was obtained by conventional or biological therapy. CONCLUSION: The finding that immune phenotype is normalized in remission suggests a link between immune phenotype and disease activity in childhood CD. Our observations support the involvement of members of the adaptive and innate immune systems in childhood CD.

Anti-microbial antibodies in celiac disease:Trick or treat?

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: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.