Assessing inflammatory bowel disease-associated antibodies in Caucasian and First Nations cohorts

BACKGROUND:

First Nation populations in Canada have a very low incidence of inflammatory bowel disease (IBD). Based on typical infections in this population, it is plausible that the First Nations react differently to microbial antigens with a different antibody response pattern, which may shed some light as to why they experience a low rate of IBD.

OBJECTIVE:

To compare the positivity rates of antibodies known to be associated with IBD in Canadian First Nations compared with a Canadian Caucasian population.

METHODS:

Subjects with Crohn’s disease, ulcerative colitis (UC), rheumatoid arthritis (RA) (as an immune disease control) and healthy controls without a personal or family history of chronic immune diseases, were enrolled in a cohort study aimed to determine differences between First Nations and Caucasians with IBD or RA. Serum from a random sample of these subjects (n=50 for each of First Nations with RA, First Nations controls, Caucasians with RA, Caucasians with Crohn’s disease, Caucasians with UC and Caucasians controls, and as many First Nations with either Crohn’s disease or UC as could be enrolled) was analyzed in the laboratory for the following antibodies: perinuclear antineutrophil cytoplasmic antibody (pANCA), and four Crohn’s disease-associated antibodies including anti-Saccharomyces cerevisiae, the outer membrane porin C of Escherichia coli, I2 – a fragment of bacterial DNA associated with Pseudomonas fluorescens, and the bacterial flagellin CBir-1. The rates of positive antibody responses and mean titres among positive results were compared.

RESULTS:

For pANCA, First Nations had a positivity rate of 55% in those with UC, 32% in healthy controls and 48% in those with RA. The pANCA positivity rate was 32% among Caucasians with RA. The rates of the Crohn’s disease-associated antibodies for the First Nations and Caucasians were comparable. Among First Nations, up to one in four healthy controls were positive for any one of the Crohn’s disease-associated antibodies. First Nations had significantly higher pANCA titres in both the UC and RA groups than Caucasians

DISCUSSION:

Although First Nation populations experience a low rate of IBD, they are relatively responsive to this particular antibody panel.

CONCLUSIONS:

The positivity rates of these antibodies in First Nations, despite the low incidence of IBD in this population, suggest that these antibodies are unlikely to be of pathogenetic significance.     

Urotensin II levels in patients with inflammatory bowel disease

BACKGROUNDPatients with inflammatory bowel disease (IBD) are associated with increased cardiovascular risk and have increased overall cardiovascular burden. On the other hand, urotensin II (UII) is one of the most potent vascular constrictors with immunomodulatory effect that is connected with a number of different cardiometabolic disorders as well. Furthermore, patients with ulcerative colitis have shown increased expression of urotensin II receptor in comparison to healthy controls. Since the features of IBD includes chronic inflammation and endothelial dysfunction as well, it is plausible to assume that there is connection between increased cardiac risk in IBD and UII.AIMTo determine serum UII levels in patients with IBD and to compare them to control subjects, as well as investigate possible associations with relevant clinical and biochemical parameters.METHODSThis cross sectional study consecutively enrolled 50 adult IBD patients (26 with Crohn’s disease and 24 with ulcerative colitis) and 50 age and gender matched controls. Clinical assessment was performed by the same experienced gastroenterologist according to the latest guidelines. Ulcerative Colitis Endoscopic Index of Severity and Simple Endoscopic Score for Crohn’s Disease were used for endoscopic evaluation. Serum levels of UII were determined using the enzyme immunoassay kit for human UII, according to the manufacturer’s instructions.RESULTSIBD patients have significantly higher concentrations of UII when compared to control subjects (7.57 ± 1.41 vs 1.98 ± 0.69 ng/mL, P < 0.001), while there were no significant differences between Crohn’s disease and ulcerative colitis patients (7.49 ± 1.42 vs 7.65 ± 1.41 ng/mL, P = 0.689). There was a significant positive correlation between serum UII levels and high sensitivity C reactive peptide levels (r = 0.491, P < 0.001) and a significant negative correlation between serum UII levels and total proteins (r = -0.306, P = 0.032). Additionally, there was a significant positive correlation between serum UII levels with both systolic (r = 0.387, P = 0.005) and diastolic (r = 0.352, P = 0.012) blood pressure. Moreover, serum UII levels had a significant positive correlation with Ulcerative Colitis Endoscopic Index of Severity (r = 0.425, P = 0.048) and Simple Endoscopic Score for Crohn’s Disease (r = 0.466, P = 0.028) scores. Multiple linear regression analysis showed that serum UII levels retained significant association with high sensitivity C reactive peptide (β ± standard error, 0.262 ± 0.076, P < 0.001) and systolic blood pressure (0.040 ± 0.017, P = 0.030).CONCLUSIONIt is possible that UII is involved in the complex pathophysiology of cardiovascular complications in IBD patients, and its purpose should be investigated in further studies.     

Prolonged QT dispersion in inflammatory bowel disease

AIM:To investigate the frequency and factors of prolonged QT dispersion that may lead to severe ventricular arrhythmias in patients with inflammatory bowel disease(IBD).METHODS:This study included 63 ulcerative colitis(UC) and 41 Crohn’s disease(CD) patients.Forty-seven healthy patients were included as the control group.Heart rate was calculated using electrocardiography,corrected QT dispersion(QTcd) and the Bazett’s formula.Homeostasis model assessment(HOMA) was used to determine insulin resistance(IR).HOMA values < 1 were considered normal and values > 2.5 indicated a high probability of IR.RESULTS:Prolonged QTcd was found in 12.2% of UC patients,and in 14.5% of CD patients compared with the control group(P < 0.05).A significant difference was found between the insulin values(CD:10.95 ± 6.10 vs 6.44 ± 3.28,P < 0.05;UC:10.88 ± 7.19 vs 7.20 ± 4.54,P < 0.05) and HOMA(CD:2.56 ± 1.43 vs 1.42 ± 0.75,P < 0.05;UC:2.94 ± 1.88 vs 1.90 ± 1.09,P < 0.05) in UC and CD patients with and without prolonged QTcd.Disease behavior types were determined in CD patients with prolonged QTcd.Increased systolic arterial pressure(125 ± 13.81 vs 114.09 ± 8.73,P < 0.01) and age(48.67 ± 13.93 vs 39.57 ± 11.58,P < 0.05) in UC patients were significantly associated with prolonged QTcd.CONCLUSION:Our data show that IBD patients have prolonged QTcd in relation to controls.The routine followup of IBD patients should include determination of HOMA,insulin values and electrocardiogram examination.     

Inflammatory bowel disease serology in Asia and the West

AIM:To study serological antibodies in Caucasians and Asians,in health and inflammatory bowel disease(IBD),in Australia and Hong Kong(HK).METHODS:Anti-glycan antibodies[anti-chitobioside(ACCA),anti-laminaribioside(ALCA)],and anti-mannobioside(AMCA),anti-Saccharomyces cervisiae(gASCA);and atypical perinuclear anti-neutrophil cytoplasmic antibody(pANCA)were tested in IBD patients,their unaffected relatives,and healthy controls in Australia and HK(China).Antibody status(positive or negative)and titre was compared between subjects of different geography,ethnicity and disease state.RESULTS:Ninety subjects were evaluated:21 Crohn’s disease(CD),32 ulcerative colitis(UC),29 healthy controls,and 8 IBD patient relatives.Forty eight subjects were Australian(29 Caucasian and 19 ethnic Han Chinese)and 42 were from HK(all Han Chinese).Caucasian CD patients had a significantly higher antibody prevalence of gASCA(67%vs 3%,P<0.001),ALCA(44%vs 6%,P=0.005),and AMCA(67%vs 15%,P=0.002),whereas HK CD patients had a higher prevalence of only AMCA(58%vs 25%,P=0.035),when compared with UC and healthy subjects in both countries.Caucasian CD had significantly higher gASCA prevalence(67%vs 0%,P<0.001)and titre(median59 vs 9,P=0.002)than HK CD patients.Prevalence and titres of ALCA,ACCA and AMCA did not differ between CD in the two countries.Presence of at least one antibody was higher in Caucasian than HK CD patients(100%vs 58%,P=0.045).pANCA did not differ between countries or ethnicity.CONCLUSION:Serologic CD responses differ between HK Asian and Australian Caucasian patients.Different genetic,environmental or disease pathogenic factors may account for these differences.     

Apolipoprotein E variants correlate with the clinical presentation of paediatric inflammatory bowel disease: A cross-sectional study

BACKGROUNDIt has been suggested that apolipoprotein E (APOE) polymorphisms are associated with the risk of developing inflammatory bowel disease (IBD) and the early age of disease onset. However, there are no reports regarding the relationship with clinical characteristics and disease severity.AIMTo summarise that APOE polymorphisms are associated with the risk of developing IBD and the early age of disease onset. METHODSIn total, 406 patients aged 3-18 with IBD (192 had ulcerative colitis and 214 had Crohn’s disease) were genotyped using the TaqMan hydrolysis probe assay. Clinical expression was described at diagnosis and the worst flare by disease activity scales, albumin and C-reactive protein levels, localisation and behaviour (Paris classification). Systemic steroid intake with the total number of courses, immunosuppressive, biological, and surgical treatment with the time and age of the first intervention were determined. The total number of exacerbation-caused hospitalisations, the number of days spent in hospital due to exacerbation, the number of relapses, and severe relapses were also estimated.RESULTSUlcerative colitis patients with the APOEε4 allele had lower C-reactive protein values at diagnosis (P = 0.0435) and the worst flare (P = 0.0013) compared to patients with the APOEε2 allele and genotype APOEε3/ε3. Crohn’s disease patients with the APOEε2 allele scored lower on the Pediatric Crohn’s Disease Activity Index at diagnosis (P = 0.0204). IBD patients with APOEε2 allele spent fewer days in the hospital due to relapse (P = 0.0440).CONCLUSION APOE polymorphisms are associated with the risk of developing IBD and the clinical expression of IBD. However, the clinical relevance of the differences identified is rather modest.     

Macrophage migration inhibitory factor gene polymorphisms in inflammatory bowel disease: An association study in New Zealand Caucasians and meta-analysis

AIM:To investigate the association of macrophage migration inhibitory factor(MIF)promoter polymorphisms with inflammatory bowel disease(IBD)risk.METHODS:One thousand and six New Zealand Caucasian cases and 540 Caucasian controls were genotyped for the MIF SNP-173G>C(rs755622)and the repeat polymorphism CATT5-8(rs5844572)using a predesigned TaqMan SNP assay and capillary electrophoresis,respectively.Data were analysed for single site and haplotype association with IBD risk and phenotype.Meta-analysis was employed,to assess cumulative evidence of association of MIF-173G>C with IBD.All published genotype data for MIF-173G>C in IBD were identified using PubMed and subsequently searching the references of all PubMed-identified studies.Imputed genotypes for MIF-173G>C were generated from the Wellcome Trust Case Control Consortium(and National Institute of Diabetes and Digestive and Kidney Diseases).Separate meta-analyses were performed on Caucasian Crohn’s disease(CD)(3863 patients,6031controls),Caucasian ulcerative colitis(UC)(1260 patients,1987 controls),and East Asian UC(416 patients and 789 controls)datasets using the Mantel-Haenszel method.The New Zealand dataset had 93%power,and the meta-analyses had 100%power to detect an effect size of OR=1.40 atα=0.05,respectively.RESULTS:In our New Zealand dataset,single-site analysis found no evidence of association of MIF polymorphisms with overall risk of CD,UC,and IBD or disease phenotype(all P values>0.05).Haplotype analysis found the CATT5/-173C haplotype occurred at a higher frequency in New Zealand controls compared to IBD patients(0.6 vs 0.01;P=0.03,OR=0.22;95%CI:0.05-0.99),but this association did not survive bonferroni correction.Meta-analysis of our New Zealand MIF-173G>C data with data from seven additional Caucasian datasets using a random effects model found no association of MIF polymorphisms with CD,UC,or overall IBD.Similarly,meta-analysis of all published MIF-173G>C data from East Asian datasets(416UC patients,789 controls)found no     

Helicobacter pylori infection and inflammatory bowel disease in Asians: A meta-analysis

AIM: To investigate the relationship between Helicobacter pylori infection and inflammatory bowel disease (IBD) in an Asian population.METHODS: The PubMed, EMBASE, and Cochrane Library databases were searched for observational studies published up until June 2014, without language restrictions. Additional references were obtained from reviewed articles.RESULTS: Ten studies involving 1299 IBD patients and 1817 controls were included in the meta-analysis (24.9% of IBD patients had H. pylori infection vs 48.3% of the controls). The pooled risk ratio for H. pylori infection in IBD patients compared with controls was 0.48 (95%CI: 0.43-0.54; P < 0.001). There was no significant heterogeneity in the included studies (I² = 21%). Egger’s linear regression indicated that there was no significant publication bias (P = 0.203).CONCLUSION: The H. pylori infection rate in Asian IBD patients is significantly lower than in non-IBD patients, indicating that infection protects against the development of IBD.     

Similar clinical characteristics of familial and sporadic inflammatory bowel disease in South Korea

AIM:To investigate differences of clinical characteristics and disease courses between familial and sporadic inflammatory bowel disease(IBD)patients.METHODS:We obtained clinical data on Crohn’s disease(CD)(n=691)and ulcerative colitis(n=1113)from a tertiary referral medical center between 2005and 2012.Seventeen patients(2.5%)with CD and27 patients(2.4%)with ulcerative colitis(UC)were identified as having a familial history of IBD,including the first and second degree relatives.For each control case,three times the number of age-,sex-,and diagnosis year-matched CD and UC patients,without a family history of IBD,were randomly selected in this case control study.RESULTS:There were no significant differences in age or main symptom at diagnosis,extraintestinal manifestation,location/extent,behavior of disease activity,number of hospitalizations,number of operations,operation type,number of relapses,or oral medical treatment between familial and sporadic CD and UC patients.Median(min-max)follow-up periods after diagnosis of familial CD and sporadic CD patients were 84(24-312)and 36(8-240)mo,respectively(P=0.008).Familial CD patients more frequently used anti-tumor necrosis factor(TNF)antibodies compared to sporadic CD patients(17.6%vs 0%,P=0.014).CONCLUSION:In conclusion,a family history of IBD does not seem to be an important predictive factor affecting clinical characteristics or disease course even if there is a more frequent use of anti-TNF antibodies in familial CD patients compared to sporadic CD patients.     

NOD2/CARD15 gene mutations in North Algerian patients with inflammatory bowel disease

AIM: To analyse allelic frequency of NOD2 gene variantsand to assess their correlation with inflammatory bowel disease(IBD) in Algeria.METHODS: We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn's disease(CD) and 46 with ulcerative colitis(UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CDassociated NOD2 variants(p.Arg702 Trp, p.Gly908 Arg and p.Leu1007 fsins C mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ2 test and Fisher's exact test where appropriate. Odds ratios(OR) and 95% confidence intervals(95%CI) were also estimated. Association analyses were performed to study the influence of these variants on IBD and on clinical phenotypes.RESULTS: The p.Arg702 Trp mutation showed the highest frequency in CD patients(8%) compared to UC patients(2%)(P = 0.09, OR = 3.67, 95%CI: 0.48-4.87) and controls(5%)(P = 0.4, OR = 1.47, 95%CI: 0.65-3.31). In CD patients allelic frequencies of p.Gly908 Arg and p.Leu1007 fsins C variants compared to HC were 3% vs 2%(P = 0.5, OR = 1.67, 95%CI: 0.44-6.34); 2% vs 1%(P = 0.4 OR = 2.69 95%CI: 0.48-14.87 respectively). In UC patients, allelic frequencies of p.Gly908 Arg and p.Leu1007 fsins C variants compared to HC were 1% vs 2%(P = 1, OR = 1.62, 95%CI: 0.17-4.74) and 2% vs 1%(P = 0.32, OR = 0.39, 95%CI: 0.05-2.87). The total frequency of the mutated NOD2 chromosomes was higher in CD(13%), than in HC(8%) and UC(5%). In addition, NOD2 variants were linked to a particular clinical sub-phenotype in CD in this Algerian cohort. As expected, the three NOD2 variants showed a significant association with CD but did not reach statistical significance, despite the fact that the allele frequency of NOD2 variants was in the range found in most of the European populations. This might be due to the non-exposure of the NOD2 carriers to environmental factors, required for the expression of the disease.CONCLUSION: Further analyses are necessary to study genetic and environmental factors in IBD in the Algerian population, using larger patient groups.     

Prevalence and associated factors of obesity in inflammatory bowel disease: A case-control study

BACKGROUNDIn recent years, an increasing prevalence of obesity in inflammatory bowel disease (IBD) has been observed. Obesity, moreover, has been directly correlated with a more severe clinical course and loss of response to treatment.AIMTo assess the prevalence and associated factors of obesity in IBD.METHODSWe collected data about IBD disease pattern and activity, drugs and laboratory investigations in our center. Anthropometric measures were retrieved and obesity defined as a body mass index (BMI) > 30. Then, we compared characteristics of obese vs non obese patients, and Chi-squared test and Student’s t test were used for discrete and continuous variables, respectively, at univariate analysis. For multivariate analysis, we used binomial logistic regression and estimated odd ratios (OR) and 95% confidence intervals (CI) to ascertain factors associated with obesity.RESULTSWe enrolled 807 patients with IBD, either ulcerative colitis (UC) or Crohn’s disease (CD). Four hundred seventy-four patients were male (58.7%); the average age was 46.2 ± 13.2 years; 438 (54.2%) patients had CD and 369 (45.8%) UC. We enrolled 378 controls, who were comparable to IBD group for age, sex, BMI, obesity, diabetes and abdominal circumference, while more smokers and more subjects with hypertension were observed among controls. The prevalence of obesity was 6.9% in IBD and 7.9% in controls (not statistically different; P = 0.38). In the comparison of obese IBD patients and obese controls, we did not find any difference regarding diabetes and hypertension prevalence, nor in sex or smoking habits. Obese IBD patients were younger than obese controls (51.2  ± 14.9 years vs 60.7 ± 12.1 years, P = 0.03). At univariate analysis, obese IBD were older than normal weight ones (51.2 ± 14.9 vs 44.5 ± 15.8, P = 0.002). IBD onset age was earlier in obese population (44.8 ± 13.6 vs 35.6 ± 15.6, P = 0.004). We did not detect any difference in disease extension. Obese subjects had consumed more frequently long course of systemic steroids (66.6% vs 12.5%, P = 0.02) as well as antibiotics such as metronidazole or ciprofloxacin (71.4% vs 54.7%, P = 0.05). No difference about other drugs (biologics, mesalazine or thiopurines) was observed. Disease activity was similar between obese and non obese subjects both for UC and CD. Obese IBD patients suffered more frequently from arterial hypertension, type 2 diabetes, non-alcoholic fatty liver disease. Regarding laboratory investigations, obese IBD patients had higher levels of triglyceridemia, fasting blood glucose, gamma-glutamyl-transpeptidase. On multivariate analysis, however, the only factor that appeared to be independently linked to obesity in IBD was the high abdominal circumference (OR = 16.3, 95%CI: 1.03-250, P = 0.04).CONCLUSIONObese IBD patients seem to have features similar to general obese population, and there is no disease-specific factor (disease activity, extension or therapy) that may foster obesity in IBD.     

Association of MYO9B gene polymorphisms with inflammatory bowel disease in Chinese Han population

AIM: To explore the association of MYO9B gene polymorphisms with clinical phenotypes and intestinal permeability of individuals with inflammatory bowel disease (IBD) in China.METHODS: A total of 442 IBD patients and 402 healthy volunteers were genotyped for two single nucleotides (rs962917 and rs1545620) using the ligase detection reaction and polymerase chain reaction. Allelic and genotype frequency analyses were performed for the two groups. Intestinal permeability was evaluated using lactulose (L) and mannitol (M) excretion. The association of MYO9B gene polymorphisms with intestinal permeability between the normal and high intestinal permeability groups was analyzed.RESULTS: Overall, there was no significant difference in the genotypic and allelic frequencies of MYO9B between IBD patients and controls. Although no association was found with ulcerative colitis in the comparison between the subgroups, the frequencies of rs962917 and rs1545620 were different in the Crohn’s disease (CD) subgroup with ileocolitis (CC vs CT and TT, P = 0.014; and AA vs AC and CC, P = 0.022, respectively). rs1545620 variants appear to be the genetic susceptibility factor for perianal disease in CD patients (AA vs AC CC, P = 0.029). In addition, the L/M ratio was significantly higher in IBD patients than in controls (0.065 ± 0.013 vs 0.020 ± 0.002, P = 0.02), but no association was found between the MYO9B gene and the L/M ratio in IBD patients.CONCLUSION: MYO9B gene polymorphisms may influence the sub-phenotypic expression of CD in China. No association between these MYO9B polymorphisms and intestinal permeability in IBD patients was found.     

Medication non-adherence in adult patients affected by inflammatory bowel disease: a critical review and update of the determining factors,consequences and possible interventions

Introduction: Achieving adherence to medications can be a serious challenge for patients affected by inflammatory bowel disease (IBD). Medical treatment is fundamental for inducing and maintaining remission, preventing flares and reducing the risk of colorectal cancer. Non-adherence may affect patients’ quality of life resulting in unfavourable treatment outcomes, more hospitalizations and higher healthcare-related costs. Recognising and improving adherence is therefore a primary aim for the treatment of IBD.

Areas covered: We critically discuss the current knowledge on medication non-adherence in adult patients affected by IBD, also mentioning a few issues concerning the paediatric and adolescent populations. In particular, we reviewed the literature focusing on the definition and detection of non-adherence, on its extent and on the possible non-modifiable and modifiable factors involved (patient-centred, therapy-related, disease-related and physician-related). Furthermore, we analysed the interventional studies performed so far. The literature review was conducted through PubMed addressing medication non-adherence in IBD, using the keywords ‘adherence’ and related terms and ‘IBD, ulcerative colitis or Crohn’s disease’.

Expert commentary: Adherence to therapy for IBD is a complex yet fundamental issue that cannot be solved by addressing a single aspect only. Future studies should focus on patient-tailored and multidimensional interventions.     

Crohn’s and colitis in children and adolescents

Crohn’s disease and ulcerative colitis can be grouped as the inflammatory bowel diseases (IBD). These conditions have become increasingly common in recent years, including in children and young people. Although much is known about aspects of the pathogenesis of these diseases, the precise aetiology is not yet understood, and there remains no cure. Recent data has illustrated the importance of a number of genes-several of these are important in the onset of IBD in early life, including in infancy. Pain, diarrhoea and weight loss are typical symptoms of paediatric Crohn’s disease whereas bloody diarrhoea is more typical of colitis in children. However, atypical symptoms may occur in both conditions: these include isolated impairment of linear growth or presentation with extra-intestinal manifestations such as erythema nodosum. Growth and nutrition are commonly compromised at diagnosis in both Crohn’s disease and colitis. Consideration of possible IBD and completion of appropriate investigations are essential to ensure prompt diagnosis, thereby avoiding the consequences of diagnostic delay. Patterns of disease including location and progression of IBD in childhood differ substantially from adult-onset disease. Various treatment options are available for children and adolescents with IBD. Exclusive enteral nutrition plays a central role in the induction of remission of active Crohn’s disease. Medical and surgical therapies need to considered within the context of a growing and developing child. The overall management of these chronic conditions in children should include multi-disciplinary expertise, with focus upon maintaining control of gut inflammation, optimising nutrition, growth and quality of life, whilst preventing disease or treatment-related complications.     

Accelerated infliximab infusions for inflammatory bowel disease improve effectiveness

AIM:To study the safety and effectiveness associated with accelerated infliximab infusion protocols in patients with inflammatory bowel disease(IBD).METHODS:Original protocols and infusion rates were developed for the administration of infliximab over 90-min and 60-min.Then the IBD patients on stable maintenance infliximab therapy were offered accelerated infusions.To be eligible for the study,patients needed a minimum of four prior infusions.An initial infusion of 90-min was given to each patient;those tolerating the accelerated infusion were transitioned to a 60-min infusion protocol at their next and all subsequent visits.Any patient having significant infusion reactions would be reverted to the standard 120-min protocol.A change in a patient’s dose mandated a single 120-min infusion before accelerated infusions could be administered again.RESULTS:The University of Virginia Medical Center’s Institutional Review Board approved this study.Fifty IBD patients treated with infliximab 5mg/kg,7.5mg/kg and 10mg/kg were offered accelerated infusions.Forty-six patients consented to participate in the study.Nineteen(41.3%) were female,five(10.9%) were African American and nine(19.6%) had ulcerative colitis.The mean age was 42.6 years old.Patients under age 18 were excluded.Ten patients used immunosuppressive drugs concurrently out of which six were taking azathioprine,three were taking 6-mercaptopurine and one was taking methotrexate.One of the 46 study patients used corticosteroid therapy for his IBD.Seventeen of the patients used prophylactic medications prior to receiving infusions;six patients received corticosteroids as pre-medication.Four patients had a history of distant transfusion reactions to infliximab.These reactions included shortness of breath,chest tightness,flushing,pruritus and urticaria.These patients all took prophylactic medications before receiving infusions.46 patients(27 males and 19 females) received a total of fifty 90-min infusions and ninety-three 60-min infusions.No infusion reactions were reported.There were no adverse events,including drug-related infections.None of the patients developed cancer of any type during the study timeframe.Total cost savings for administration of the both 90-min and 60-min accelerated infusions compared to standard 120-min infusions was estimated to be $53 632($116 965 vs $63 333,P=0.001).One hundred and eighteen hours were saved in the administration of the accelerated infusions(17 160 min vs 10 080 min,P=0.001).In the study population,overweight females [body mass index(BMI)>25.00kg/m2] were found to have statistically higher BMIs than overweight males(mean BMI 35.07±2.66kg/m2 vs 30.08±0.99kg/m2,P=0.05),finding which is of significance since obesity was described as being one of the risk factors for Crohn’s disease.CONCLUSION:We are the first US group to report substantial cost savings,increased safety and patient satisfaction associated with accelerated infliximab infusion.     

Serological profiling of Crohn’s disease and ulcerative colitis patients reveals anti-microbial antibody signatures

BACKGROUNDThe healthcare burden of inflammatory bowel disease (IBD) is rising globally and there are limited non-invasive biomarkers for accurate and early diagnosis. AIMTo understand the important role that intestinal microbiota play in IBD pathogenesis and identify anti-microbial antibody signatures that benefit clinical management of IBD patients.METHODSWe performed serological profiling of 100 Crohn’s disease (CD) patients, 100 ulcerative colitis (UC) patients and 100 healthy controls against 1173 bacterial and 397 viral proteins from 50 bacteria and 33 viruses on protein microarrays. The study subjects were randomly divided into discovery (n = 150) and validation (n = 150) sets. Statistical analysis was performed using R packages. RESULTSAnti-bacterial antibody responses showed greater differential prevalence among the three subject groups than anti-viral antibody responses. We identified novel antibodies against the antigens of Bacteroidetes vulgatus (BVU_0562) and Streptococcus pneumoniae (SP_1992) showing higher prevalence in CD patients relative to healthy controls. We also identified antibodies against the antigen of Streptococcus pyogenes (SPy_2009) showing higher prevalence in healthy controls relative to UC patients. Using these novel antibodies, we built biomarker panels with area under the curve (AUC) of 0.81, 0.87, and 0.82 distinguishing CD vs control, UC vs control, and CD vs UC, respectively. Subgroup analysis revealed that penetrating CD behavior, colonic CD location, CD patients with a history of surgery, and extensive UC exhibited highest antibody prevalence among all patients. We demonstrated that autoantibodies and anti-microbial antibodies in CD patients had minimal correlation.CONCLUSIONWe have identified antibody signatures for CD and UC using a comprehensive analysis of anti-microbial antibody response in IBD. These antibodies and the source microorganisms of their target antigens improve our understanding of the role of specific microorganisms in IBD pathogenesis and, after future validation, should aid early and accurate diagnosis of IBD.     

Mucosal bacterial microflora and mucus layer thickness in adolescents with inflammatory bowel disease

AIM: To assess the mucosa-associated bacterial microflora and mucus layer in adolescents with inflammatory bowel disease (IBD).METHODS: Sixty-one adolescents (mean age 15 years, SD ± 4.13) were included in the study. Intestinal biopsies from inflamed and non-inflamed mucosa of IBD patients and from controls with functional abdominal pain were cultured under aerobic and anaerobic conditions. The number of microbes belonging to the same group was calculated per weight of collected tissue. The mucus thickness in frozen samples was measured under a fluorescent microscope.RESULTS: The ratios of different bacterial groups in inflamed and non-inflamed mucosa of IBD patients and controls were specific for particular diseases. Streptococcus spp. were predominant in the inflamed mucosa of Crohn’s disease (CD) patients (80% of all bacteria), and Lactobacillus spp. were predominant in ulcerative colitis patients (90%). The differences were statistically significant (P = 0.01-0.001). Lower number of bifidobacteria was observed in the whole IBD group. A relation was also found between clinical and endoscopic severity and decreased numbers of Lactobacillus and, to a lesser extent, of Streptococcus in biopsies from CD patients. The mucus layer in the inflamed sites was significantly thinner as compared to controls (P = 0.0033) and to non-inflamed areas in IBD patients (P = 0.031).CONCLUSION: The significantly thinner mucosa of IBD patients showed a predominance of some aerobes specific for particular diseases, their numbers decreased in relation to higher clinical and endoscopic activity of the disease.     

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.     

Beliefs About Medicines and Adherence to Treatment in Turkish Patients with Inflammatory Bowel Disease

Background:Although studies are investigating the perception and beliefs about treatment and adherence to treatment in different societies related to inflammatory bowel disease, there are no studies on this subject in Turkish people with different sociocultural structures. In our study, we aimed to evaluate the beliefs about treatment and its effect on adherence to treatment in the Turkish population with inflammatory bowel disease.Methods:In the study, the “Medication Adherence Report Scale” and “Beliefs about Medicines Scale” scales were used to evaluate the treatment compliance and perception and beliefs about treatment. Characteristics that could affect treatment compliance were evaluated by statistical analysis.Results:A total of 253 patients, 167 with ulcerative colitis and 86 with Crohn’s disease, were included in the study. The non-adherence rate to the treatment was found as 41.9% in ulcerative colitis and 24.4% in Crohn’s disease (P = .006). Intentional (29.3% in ulcerative colitis and 16.3% in Crohn’s disease [P = .031] and unintentional non-adherence to treatment (28.1% in ulcerative colitis, 16.3% in Crohn’s disease [P = .037] were significantly higher in ulcerative colitis than in Crohn’s disease. Female gender (odds ratio = 2.59, P = .005), low education level (odds ratio = 4.8, P = .015), distal involvement in ulcerative colitis (P = .014), and thoughts about the disease would last too soon in Crohn’s disease (odds ratio = 4.17, P = .049) were risk factors for non-adherence to treatment.Conclusion:The negative perception of treatment in inflammatory bowel disease affects adherence to the treatment. Considering some social factors that affect adherence to the treatment and taking measures to enhance the adherence to treatment will increase the success of treatment.     

Serum concentrations of insulin-like growth factor-binding protein 5 in Crohn’s disease

AIM:To investigate serum insulin-like growth factorbinding protein 5(IGFBP-5)levels and intestinal IGFBP-5expression in patients with Crohn’s disease(CD).METHODS:We analyzed the serum concentrations and intestinal expression of IGFBP-5 in 42 patients with CD,of whom 26 had endoscopically or radiologically proven stricture formation.Nine of the 42 patients had active disease,with a Crohn’s disease activity index>150.Serum IGFBP-5 levels were analyzed in 20 healthy controls matched by sex and age to the CD patients.Serum IGFBP-5 was measured using an enzyme-linked immunosorbent assay.Intestinal tissue was obtained from patients through endoscopic biopsies.IGFBP-5expression was detected using immunohistochemistry and was scored semiquantitatively.RESULTS:The median serum IGFBP-5 concentrations of CD patients were significantly lower compared with healthy controls[median 7.2(IQR:5.5-11.3)ng/mL vs 11.3(8.0-44.6)ng/mL,P<0.001].There was no significant difference between median serum IGFBP-5levels in CD patients with or without stricture formation[6.9(5.5-11.3)ng/mL vs 7.8(5.3-10.1)ng/mL,P=0.815].The serum IGFBP-5 levels were not significantly different between patients with active disease and inactive disease[7.2(6.5-7.6)ng/mL vs 7.2(5.5-11.3)ng/mL,P=0.890].However,a significant correlation was observed between serum IGFBP-5 levels and platelet count(PLT)(r=0.319,P=0.0395).No significant correlation was found between tissue IGFBP-5 immunohistochemical staining intensity scores and serum IGFBP-5 levels.No significant difference was found when comparing the serum IGFBP-5 levels among the patients with different tissue IGFBP-5 staining scores(absent/very weak,weak,moderate or strong).There was a significant correlation between tissue IGFBP-5staining scores and white blood cell count(r=0.391,P=0.01)and PLT(r=0.356,P=0.021).CONCLUSION:Our results indicate that serum IGFBP-5 concentrations were lower in CD patients compared to healthy controls regardless of disease activity or the presence of stricture formation.