Journal of Crohn's and Colitis - Articles in Press

Management of inflammatory bowel disease in pregnancy - Corrected Proof

2012-05-18

Abstract: Background and Aims: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients’ family planning decisions. Management of IBD in pregnancy requires a challenging balance between optimal disease control and drug safety considerations.This article aims to provide a framework for clinical decision making in IBD based on review of the literature on pregnancy-related topics.Methods: Medline searches with search terms ‘IBD’, ‘Crohn's disease’ or ‘ulcerative colitis’ in combination with keywords for the topics fertility, pregnancy, congenital abnormalities and drugs names of drugs used for treatment of IBD.Results: IBD patients have normal fertility, except for women after ileal pouch-anal anastomosis (IPAA) and men under sulfasalazine treatment. Achieving and maintaining disease remission is a key factor for successful pregnancy outcomes in this population, as active disease at conception carries an increased risk of preterm delivery and low birth weight.Clinicians should discuss the need for drug therapy to maintain remission with their patients in order to ensure therapy compliance. Most IBD drugs are compatible with pregnancy, except for methotrexate and thalidomide. If possible, anti-TNF therapy should be stopped by the end of the second trimester and the choice of delivery route should be discussed with the patient.Conclusions: Disease control prior to conception and throughout pregnancy is the cornerstone of successful pregnancy management in IBD patients.

Reply to Dr. McNabb-Baltar's letter - Corrected Proof

Ashwin N. Ananthakrishnan — 2012-05-17

We thank the interest shown in our manuscript by Dr. McNabb-Baltar and agree that identification of risk factors for infectious complications in patients with inflammatory bowel disease (IBD) is an important area of research.

Reply to Dr. Chouchana's letter - Corrected Proof

Ulf Hindorf, Malin Lindqvist Appell — 2012-05-17

We would like to thank Dr. Chouchana for the comments on our manuscript and thereby giving us the opportunity to discuss this important topic again. The thiopurine metabolism is complex and several enzymes, besides TPMT, are probably of clinical importance. Clinicians thus need to be aware of the limitations of a TPMT test and use it in a correct clinical context.

Proinflammatory cytokines induce crosstalk between colonic epithelial cells and subepithelial myofibroblasts: Implication in intestinal fibrosis - Corrected Proof

2012-05-11

Abstract: Background and aims: Colonic epithelial cells and adjacent subepithelial myofibroblasts are important counterparts in the pathogenesis of intestinal inflammation and fibrosis. We investigated the possible crosstalk between them, whilst focusing on the mucosal inflammation pathways that potentially trigger intestinal fibrosis.Methods: We studied the effects of proinflammatory cytokines (IL-1α, TNF-α, IFN-γ) on human colonic epithelial cell lines and the effects of epithelial cell-conditioned media on primary human colonic subepithelial myofibroblasts isolated from normal controls or patients with inflammatory Crohn's disease along with the corresponding 18CO cell line. Readouts included production of TGF-β and TIMP-1, total collagen synthesis, matrix metalloproteinases MMP-2 and MMP-9 and myofibroblast migration/mobility.Results: Proinflammatory cytokines upregulated TGF-β and TIMP-1 in colonic epithelial cells. Conditioned medium from these epithelial cell cultures induced production of MMP-9 and collagen and inhibited the migration/mobility of subepithelial myofibroblasts. MMP-9 production depended on endothelin receptor A signalling on responding myofibroblasts. Collagen up-regulation was independent of TGF-β, CTGF, TF and endothelin. Subepithelial myofibroblasts isolated from Crohn's disease patients had similar responses to those isolated from normal controls, with the exception of higher basal collagen production.Conclusions: Our study indicates that colonic epithelial cells may respond to an inflammatory milieu by inducing myofibroblast functions similar to those observed during intestinal fibrosis.

The “hygiene hypothesis” in IBD - Corrected Proof

Richard B. Gearry, Andrew J. Dodgshun — 2012-05-07

We read with interest the paper by Castiglione et al. investigating the role of hygiene hypothesis related as potential risk factors for the development of inflammatory bowel disease (IBD). This study confirmed the association with established risk factors (cigarette smoking, familial aggregation and appendicectomy) and IBD although not the findings of others. While this was a large study, the use of hospital employee controls may have introduced bias as they were not randomly selected from the population from that of the cases. Furthermore, the reporting of some variables from childhood may be subject to recall bias as the events are distant in time and may not be consistently remembered.

Positive serum IgA-tissue-transglutaminase antibodies are not all but enough to diagnose coeliac disease without a small bowel biopsy - Corrected Proof

Fabio Panetta, Francesca Ferretti, Antonella Diamanti — 2012-05-03

We have read with great interest the article by Fernández-Bañares and coworkers about the attitude of the tissue-transglutaminase antibodies of IgA class (tTG) in implementing the diagnosis of celiac disease (CD) without biopsy. In this paper the authors report that no cut-off level of tTG is associated with a positive predictive value (PPV) of 100% and that the CD diagnosis also requires biopsy in patients with strongly positive tTG. As reported in this work, in the past years several authors have questioned the requirement for small bowel biopsy to establish the diagnosis of CD in every case. This is an interesting topic mainly at pediatric age and recently the ESPGHAN has proposed a new approach that does not include the biopsy to the diagnosis of CD in children and adolescents with several characteristics. In summary, biopsy might be avoided in those patients with a compatible clinical picture, positive celiac genetics (HLA-DQ2 and/or HLA-DQ8), and high IgA anti-tTG levels (N10× upper normal limit), verified by anti-endomysium antibodies (EMA) positivity. The results presented by Fernandez-Banares et al. seem to not support the ESPGHAN indications that instead meet our experience as reported in two previously published papers. In both our previous reported surveys, including only subjects with symptoms suggestive of CD, we found a post-test probability of 99% and PPV of 100% as for tTG≥20IU/mL assessed by ELISA test, as for tTG≥16AU/mL assessed by chemiluminescence test. In these studies the patients positive to tTG also underwent EMA detection; all patients underwent duodenal biopsy. The main results of these studies are summarized in . In line of our results, we concluded that, in pediatric patients with symptoms suggesting CD, high levels of tTG with positive EMA could lead to avoid the duodenal biopsy. The main difference from our experience compared with that reported by Fernández-Bañares and coworkers is represented by the inclusion criteria of the patients. In this survey all adult and pediatric CD patients with tTG≥7IU/mL, measured in the period between January 2008 and December 2010, whom a small bowel biopsy was performed, were recruited. The authors report that all patients were on a gluten-containing diet at inclusion, but did not refer their clinical symptoms. The presence of clinical symptoms suggestive of CD can increase the PPV of the screening test. The ESPGHAN guidelines indeed suggest that it may be possible to avoid the biopsy only in the presence of clinical symptoms with positive screening test. The way of patients' selection in this study could have reduced therefore the attitude of positive tTG in predicting the results of the biopsy.

Elevated immunoglobulin G4 level is associated with reduced colectomy-free survival in patients with primary sclerosing cholangitis and ulcerative colitis - Corrected Proof

2012-05-03

Abstract: Background and aim: Patients with primary sclerosing cholangitis (PSC) and elevated immunoglobulin (Ig) G4 have been shown to have more severe disease with a shorter time to orthotopic liver transplantation (OLT). The aim of the study was to investigate the clinical outcomes of PSC and UC in patients with elevated serum IgG4.Methods: We analyzed data from 50 patients with PSC and known serum levels of IgG4. They were divided into groups called high IgG4 (>112IU/L; n=10) or normal IgG4 (n=40). We compared the requirement of OLT and colectomy between groups.Results: High IgG4 was found in 10 PSC patients (20%). UC was associated in 9/10 patients with high IgG4 vs. 32/40 patients with normal IgG4 (p=0.67). Patients with high IgG4 were younger at PSC diagnosis (28.1±13.9 vs. 37.6±13.4years, P=0.04), more likely to have backwash ileitis (7/9 vs. 12/32, P<0.001) and UC flares (median of 5.5 vs. 1.5, P=0.02). Kaplan–Meier curve analysis showed that patients with elevated IgG4 had reduced colectomy-free survival than patients with normal IgG4 (Log Rank p<0.001). The median time to colectomy was 5years from UC diagnosis in high IgG4 group vs. 12years in the normal IgG4 group (p=0.01).Conclusions: Elevated IgG4 was seen in a small number of PSC patients. Most of these patients had associated UC, were younger at the time of PSC diagnosis, more likely to have backwash ileitis and had reduced colectomy-free survival than patients with normal IgG4.

Dysplasia and colorectal cancer in a patient with ulcerative colitis and primary sclerosing cholangitis: A case report and a short review of the literature - Corrected Proof

2012-05-01

Abstract: Primary sclerosing cholangitis is a chronic progressive disorder which involves the medium size and large ducts in the intrahepatic and extrahepatic biliary tree. The great majority of cases have underlying inflammatory bowel disease, mainly ulcerative colitis. A higher risk of colorectal cancer has been described among ulcerative colitis patients with primary sclerosing cholangitis. Here we report a case of a primary sclerosing cholangitis in a young male with a newly diagnosed ulcerative colitis presenting with colonic dysplasia. Surveillance for colorectal cancer should be strongly recommended in this group of patients.

Incidence of inflammatory bowel disease in the province of Styria, Austria, from 1997 to 2007: A population-based study - Corrected Proof

2012-04-30

Abstract: Background: The incidence of inflammatory bowel disease (IBD) varies widely between different countries. This large variation is also observed for the incidence of its main two forms, ulcerative colitis (UC) and Crohn's disease (CD). Controversy exists whether IBD incidence is increasing, especially in western countries. Currently no data are available for Austria. This study therefore aimed to evaluate for the first time the incidence of IBD over an eleven-year period in Styria, a province of Austria with a population of 1.2million.Methods: All patients with an initial diagnosis of IBD between 1997 and 2007, who were Styrian residents, were eligible for this retrospective study. Data were acquired from electronically stored hospital discharge reports and individual reports by patients and physicians. According to population density Styria was divided into two rural and one urban area.Results: Throughout the study period 1527 patients with an initial diagnosis of IBD were identified. The average annual incidence was 6.7 (95% CI 6.2–7.1) per 100,000 persons per year for CD and 4.8 (95% CI 4.5–5.2) for UC. The average annual incidence increased significantly (p<0.01) for both diseases during the 11year study period. Median age at initial diagnosis was 29years (range 3–87) for CD and 39years (range 3–94) for UC. At diagnosis, 8.5% of all IBD patients were <18years of age. The incidence of both CD and UC was significantly higher in the urban area than in rural areas (CD: 8.8, 95% CI 7.8–9.8 versus 5.5, 95% CI 4.7–6.4 and 5.9, 95% CI 5.3–6.7; [p<0.001]; UC: 5.8, 95% CI 5.1–6.6 versus 4.0, 95% CI 3.4–4.7 and 4.7, 95% CI 4.1–5.4; [p=0.04]).Conclusion: We observed an overall increase in the incidence of ulcerative colitis and Crohn's disease in a part of Austria during an eleven year period. IBD was more predominant in the largest urban area than in rural areas.

Contrast-enhanced ultrasonography: Usefulness in the assessment of postoperative recurrence of Crohn's disease - Corrected Proof

2012-04-30

Abstract: Aim: The aim of this study was to assess whether the contrast-enhanced ultrasonography (CEUS) can increase the value of the ultrasonography in the study of postoperative recurrence of Crohn's disease (CD).Materials and methods: 60 patients with CD who had previously undergone ileocolic resection underwent prospectively both CEUS and colonoscopy within a 3-day period. The sonographic examination included evaluation of bowel wall thickness, transmural complications, colour Doppler grade and contrast-enhanced US. In addition a sonographic score was established. The capacity of CEUS to diagnose endoscopic recurrence, as well as its severity, was assessed by calculating the sensitivity, specificity and positive and negative predictive values, accuracy and odds ratio, with their respective 95% confidence intervals. The areas under the receiver operating characteristic (ROC) curves were also calculated.Results: 49 out of 60 patients showed endoscopic postoperative recurrence. Severe endoscopic recurrence was present in 34 patients (57%). Classic ultrasound parameters (wall thickness >3mm and colour Doppler flow) revealed an accuracy of 88.3% for the diagnosis of recurrence. Sonographic score 2, including thickness >5mm or contrast enhancement >46%, improved the results with a sensitivity, specificity and accuracy of 98%, 100% and 98.3%, respectively, in the diagnosis of endoscopic recurrence. The area under the ROC curve was 0.99, in remarkable agreement with endoscopy (k: 0.946). Sonographic score 3, including thickness >5mm, contrast enhancement >70% or fistula identified 32 out of 34 (94.1%) severe endoscopic recurrences. The area under the ROC curve was 0.836, in good agreement with endoscopy (k: 0.688).Conclusion: CEUS shows excellent sensitivity and specificity for the diagnosis of postoperative recurrence in CD and can also detect severe recurrences.

TPMT status determination: The simplest is the most effective? - Corrected Proof

Laurent Chouchana, Celine Narjoz, Marie-Anne Loriot — 2012-04-30

We carefully read the article by Hindorf and Appell stating that genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase (TPMT) function. As evidence since many years, TPMT status should be determined before a thiopurine treatment to identify patients at risk for severe adverse events, as bone marrow suppression, and to propose an individualized dosage. Hindorf and Appell mentioned “it is not reasonable to check both genotype and phenotype in all patients”. We agree with that statement but we are concerned by the conclusions drawn by the authors and the choice for genotyping as primary choice.

Reply to Dr. Panetta et al.'s letter - Corrected Proof

Fernando Fernández-Bañares, Mercé Rosinach, Maria Esteve — 2012-04-30

Panetta et al. describe that a tTG value of around 3×upper normal limit (using an ELISA commercial kit by Liaison, DiaSorin S.p.a., Salugia, Italy) was associated with a post-test probability of celiac disease (CD) of 99% and a PPV of 100%. This is in contrast with our results, since no cut-off level of tTG (Varelisa, CelikeyTM, Phadia AB, Freiburg, Germany) was associated with a PPV of 100%. They argue that the differences between both studies could be that our patients were no symptomatic. However, this was not true. All patients in our study, also those with either Marsh 0 or Marsh 1 type lesions, had clinical symptoms who improved with a gluten-free diet (see the CD diagnosis paragraph and the results section). We and also others have described some patients with no or minor intestinal damage (Marshes 0 and 1) who had high titres of tTG. In our series, a cut-off of 80U/mL (11.4×upper normal limit) was associated with the higher PPV value of 98.6%. This cut-off level was associated with a post-test probability near 98% for those situations with a pre-test probability of CD of 30% or higher. However, in the most frequent clinical situations, which in general have a pre-test probability <10%, the post-test probability was 90% or less.

Previous infliximab therapy and postoperative complications after proctocolectomy with ileum pouch anal anastomosis - Corrected Proof

2012-04-27

Abstract: Background and aims: It is unclear whether infliximab treatment induces increased complication rates after surgery for ulcerative colitis. Aim was to compare complication rates after pouch surgery in refractory ulcerative colitis patients with versus without previous infliximab therapy.Methods: We performed a retrospective study evaluating all patients who underwent an ileoanal J-pouch for refractory ulcerative colitis over a four-year period. Postoperative complications, infliximab use and time between last infliximab administration and restorative surgery were assessed. 1-stage procedures (proctocolectomy with pouch, with or without temporary diversion) and 2-stage procedures (emergency colectomy and subsequent completion proctectomy with pouch, with or without temporary diversion) were analyzed separately.Results: Seventy-two patients were included; 33 underwent 1-stage procedure and 39 had 2-stage surgery. In the 1-stage group, 21 patients (64%) had previous infliximab therapy (median time between last infusion and surgery: 7.1 months (IQR 2.6-8.3)). Infliximab-treated patients had higher incidence of pelvic sepsis (5/21 vs. 0/12; risk difference 24%; 95% CI: 6 to 42, p=0.067) and non-infectious complications (8/21 vs. 1/12; risk difference 30%; 95% CI: 4 to 56, p=0.065). In the 2-stage group, 17 (44%) had previous infliximab therapy (median time between last infusion and surgery: 11.8 months (IQR 7.3-15.5)). Total, infectious, non-infectious complication rates and pelvic sepsis rates were similar for infliximab and non-infliximab patients in the 2-stage group.Conclusions: This small study suggests that infliximab use prior to 1-stage restorative proctocolectomy in patients with UC is associated with increased incidence of pelvic sepsis. A 2-stage procedure in these patients should be considered.

Does active smoking really influence the course of Crohn's disease? A retrospective observational study - Corrected Proof

2012-04-27

Abstract: Background: Active smoking has been associated with a higher risk of developing Crohn's disease (CD). However, its impact on clinical outcomes has been controversial among studies.Aims: To evaluate the influence of active smoking on initial manifestations of CD, the development of disease-related complications, and therapeutic requirements.Methods: Patients diagnosed with CD within a ten-year period (1994–2003) were identified. Clinical and therapeutic features until October 2008 or loss of follow-up were recorded. Smoking status was assessed at each major disease-related event (e.g. penetrating and stricturing complications, perianal disease, intestinal resection, introduction of immunomodulators or biological agents).Results: A total of 259 patients were included in the study with a median follow-up period of 91months. At diagnosis, 50.5% were active smokers and only 12% of them quit smoking during follow-up, mostly after a major disease-related event occurred. Smoking at diagnosis was not associated with a particular CD presentation. Active smoking did not influence the development of strictures, intraabdominal and perianal penetrating complications, or increased resectional surgery, biological therapy or immunomodulators requirements.Conclusions: Patients who develop CD while smoking seem to have a similar disease course to those who never smoked.

Immunohistochemical search for viral and bacterial antigens in Crohn's disease - Corrected Proof

William S. Magin, Herbert J. Van Kruiningen, Jean-Frédéric Colombel — 2012-04-27

Abstract: Background: Recent studies show that diseased intestinal tissues of patients with Crohn's disease (CD) contain obstructed lymphatics, granulomas, and tertiary lymphoid organs, representing responses to persistent antigen.Methods: Forty-seven tissue sections from 28 CD patients and 20 tissue sections from 17 control patients were studied. Tissues were immunostained with antibody directed against adenovirus, Epstein-Barr virus, herpes simplex virus I, parvovirus B19, Listeria monocytogenes, Escherichia coli, Clostridium perfringens, and Mycobacterium avium subspecies paratuberculosis.Results: There was no evidence of adenovirus, Epstein-Barr virus, parvovirus B19, or M. avium subsp. paratuberculosis in the tissues. Clostridia were positively stained in the mucus of 18.5% of CD patients versus 35.3% of controls and in the tissue of 11.1% of CD patients but in no controls.Immunoreactivity to listeria antibody occurred in the mucus of 3.7% of CD patients and in 5.9% of controls while it occurred in the tissue of 37.0% of CD patients and 29.4% of controls. E. coli occurred in the mucus of 48.1% CD and 64.7% controls and in the tissue of 18.5% and 5.9% respectively.Conclusions: Of the agents demonstrated in this search, none was located in granulomas or inflamed lymphatics. Finding the common gut microbes, E. coli and clostridia, in the mucus of patients and controls was not unexpected. The minor focal staining of E. coli and clostridia does not suggest a primary role for these pathogens in CD. Positive staining for listeria in patients and controls may very well represent cross reactivity rather than specific identification.

Probable diffuse retinopathy caused by adalimumab in a patient with Crohn's disease - Corrected Proof

2012-04-26

Abstract: Adalimumab is a tumor necrosis factor-α (TNF-α) antagonist used to treat several immunologic diseases. It is believed that unexpected adverse events related to anti-TNF drugs will occur as administration of this drug becomes more widespread. We report the case of a 37-year-old woman who complained of nonspecific abnormalities of vision in both eyes one month after beginning treatment with adalimumab for Crohn's disease. The results of the initial ophthalmologic examination were normal. The visual fields showed diffuse and severe depression in both eyes. Other diseases that could have caused the visual field defects were ruled out. The results of electrophysiological tests were compatible with diffuse bilateral retinopathy. Treatment with adalimumab was discontinued. Six months later, visual field loss persists, although it has improved slightly. To our knowledge, this is the first report of diffuse retinopathy probable caused by systemic administration of adalimumab. This form of retinal toxicity should be considered in patients with disorders of vision treated with this drug.

Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn's patients - Corrected Proof

2012-04-26

Abstract: Background and aims: Adalimumab is efficacious in inducing and maintaining remission in Crohn's disease but dose escalation is needed in 30–40% after 1year. Attempts for dose de-escalation have not been studied. This study aimed to assess the need for, predictors, and outcome of dose escalation and de-escalation in a large cohort of adalimumab treated Crohn's patients.Methods: All consecutive patients treated with open label adalimumab for active Crohn's disease from the participating centres were included in this cohort study. A detailed retrospective chart review was performed to look for possible factors predicting outcome.Results: Eighty four percent of 720 patients had a primary response and were followed up for a median of 14months. Thirty four percent needed escalation after a median of 7months (0–55months). Multivariate predictors for dose escalation were the following: prior anti-TNF use (p<0.0001), no concomitant azathioprine or <3m (p<0.02) and abnormal CRP at start (p<0.05). Dose escalation re-induced response for at least 6months in 67%. Only abnormal CRP at start correlated with failure of dose escalation (p=0.02). Dose de-escalation was attempted in 54% and was successful in 63%. After a median follow-up of 14m adalimumab was discontinued in 29% of patients.Conclusion: In this study real life nationwide cohort of Crohn's patients treated with adalimumab dose escalation was needed in 34% and was successful in 67%. Dose de-escalation was attempted in 54% and was successful in 63%. Overall 71% of patients maintained long term response on adalimumab.

Reply to Dr. Vitek's letter - Corrected Proof

Hilbert S. de Vries, Wilbert H.M. Peters, Dirk J. de Jong — 2012-04-25

We thank you for the opportunity to respond to the interesting letter by Dr. Vitek, regarding our results on the common UGT1A1*28 allele in the UGT1A1 gene which is related to hyperbilirubinemia and its possible protective effect for developing Crohn's disease. In our study, homozygosity for the UGT1A1*28 allele was found to protect against Crohn's disease. Since homozygosity for the UGT1A1*28 allele in Caucasians is associated with Gilbert's syndrome, which is characterized by hyperbilirubinemia, it was hypothesized by us that bilirubin, being an anti-oxidant, protects against Crohn's disease. However, serum or plasma levels of bilirubin were not measured in our study. Several studies have reported the association between the UGT1A1 promoter genotype and serum bilirubin levels, as been summarized in a recent meta-analysis by Horsfall et al. Dr. Vitek and co-workers published results of a pilot study, demonstrating a direct association between low bilirubin levels and Crohn's disease. This abstract unfortunately was not available to us, however these results apparently could be confirmed in a larger study, yet to be published. We did not report serum or plasma levels of bilirubin in our paper. We retrospectively were able to obtain data on bilirubin levels of a small number of patients from their medical files, showing approximately 30% higher bilirubin levels in patients homozygous for the UGT1A1*28 allele as compared to patients homozygous for the wildtype UGT1A1*1 allele. However, these numbers were very small. Furthermore, while the bilirubin levels were measured on clinical indications and only in a small number of patients, this retrospective investigation introduces a major source of bias. Therefore we did not add this information to our manuscript. We are looking forward to the interesting results to be reported by Dr. Vitek with regard to low serum bilirubin levels in patients with Crohn's disease. An interesting follow up question for their study might be to genotype their patients with respect to the UGT1A1*28 polymorphism.

Severe adalimumab-induced thrombocytopenia in a patient with Crohn's disease - Corrected Proof

M.J. Casanova, M. Chaparro, S. Martínez, I. Vicuña, J.P. Gisbert — 2012-04-25

Abstract: Crohn's disease is a chronic transmural inflammatory disorder characterized by inflammation of the intestine. Anti-TNF-α drugs are used for induction and maintenance of remission in patients with this condition. Thrombocytopenia is an uncommon side effect of treatment with anti-TNF-α drugs. We report the case of a 71-year-old woman diagnosed with Crohn's disease who developed severe adalimumab-induced thrombocytopenia and who did not respond to standard therapy for thrombocytopenia.

Single port laparoscopic subtotal colectomy and ileostomy in an adolescent with ulcerative colitis - Corrected Proof

2012-04-20

Abstract: Introduction: Single port laparoscopic surgery has been increasingly used for complex surgical procedures. To our knowledge, this is the first published report of a single port laparoscopic subtotal colectomy and ileostomy in an adolescent patient with ulcerative colitis.Case report: A 13-year old female patient with ulcerative colitis resistant to maximal medical therapy underwent a single port laparoscopic subtotal colectomy and ileostomy. Both the procedure and the postoperative recovery were uneventful and the patient was discharged home on the sixth postoperative day. Follow-up at 3 and 8weeks after surgery identified no early complications with a 4kg weight gain.Discussion: Single port laparoscopic surgery is feasible in the adolescent population if there is appropriate surgical expertise and strict patient selection.

Efficacy of Adalimumab as a long term maintenance therapy in ulcerative colitis - Corrected Proof

2012-04-20

Abstract: Introduction: Adalimumab is a recombinant human IgG1 monoclonal antibody to TNF-alpha. There are limited data with regard to its efficacy in ulcerative colitis. We report experience of adalimumab in ulcerative colitis in a single centre with a focus on the ability of this agent to maintain response and avoid colectomy in the medium to long-term.Methods: Twenty-three ulcerative colitis patients (mean age 32years; 7 female) who received adalimumab were identified from a prospectively maintained database of over 2700 IBD patients. The primary study endpoint was treatment failure defined as discontinuation of adalimumab due to lack of efficacy, as defined by requiring an alternative maintenance therapy or colectomy, or intolerance. Colectomy rate was recorded as a secondary endpoint.Results: Most patients (96%) had received immunosuppressants prior to adalimumab therapy (infliximab 20/23 87%). Sixteen of 23 patients (70%) discontinued adalimumab. Six primary failures, 8 secondary loss of response, one had unacceptable side effects and one discontinued treatment after 6months but remains in remission. Overall estimated cumulative treatment failure rates at 6, 12 and 24months were 50%, 65% and 72% respectively. Median follow-up in patients continuing adalimumab is 23months (IQR 17–31months). Treatment failure was unrelated to patient age, gender, disease extent, smoking status or CRP. Colectomy free survival was 59% at 2years. No patient experienced a major adverse event.Conclusion: Adalimumab shows some efficacy as a maintenance strategy in Ulcerative Colitis, but only a limited proportion of patients remain well on continued treatment at 2years.

Inflammatory bowel disease and lupus: A systematic review of the literature - Corrected Proof

Konstantinos H. Katsanos, Paraskevi V. Voulgari, Epameinondas V. Tsianos — 2012-04-16

Abstract: Coexistence of systemic lupus erythematosus (SLE) should be considered in patients with inflammatory bowel disease (IBD) and complex extraintestinal manifestations and the diagnosis of IBD could be established either before or after the diagnosis of SLE. Differential diagnosis of concomitant SLE and IBD is difficult and should always exclude infectious conditions, lupus-like reactions, visceral vasculitis and drug-induced lupus.The underlying mechanism by which 5-ASA/sulphasalazine induces SLE or lupus-like syndromes is not clear and high awareness for possible predictive factors is demanded for early prevention.In most cases the symptoms from drug-induced lupus have been reversible after the discontinuation of the drug and response to steroids is favorable. Treatment of patients co-diagnosed with SLE and IBD may include corticosteroids, immunosupressants and hydroxychloroquine.In severe lupus and IBD patients cyclophosphamide pulse may be of benefit while infliximab may be beneficiary in patients with lupus nephritis. However, the role TNFalpha plays in humans with SLE and IBD is controversial and data on the likely effects of blocking TNFalpha on anti-DNA autoantibody production is always of interest.

Low mannose-binding lectin (MBL) is associated with paediatric inflammatory bowel diseases and ileal involvement in patients with Crohn disease - Corrected Proof

2012-04-16

Abstract: Background: Mannose-binding lectin (MBL) is a pattern-recognition molecule of the innate immune system and may be involved in the pathogenesis of inflammatory bowel disease (IBD). Our aim was to assess the prevalence of MBL deficiency in a cohort of patients with paediatric-onset IBD and study whether it is associated with the clinical manifestations, serum antibody formation, or genetic factors.Methods: This prospective study included 159 paediatric patients (mean age: 14.0years) with IBD [107 patients with Crohn disease (CD) and 52 patients with ulcerative colitis (UC)]. Furthermore, 95 controls were investigated. Serum samples were determined for MBL by enzyme-linked immunosorbent assay (ELISA) and for serologic markers [autoantibodies against Saccharomyces cerevisiae (ASCA) and perinuclear components of neutrophils (pANCA)] by indirect immunofluorescent assay. NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism.Results: The MBL serum concentration was significantly lower in IBD patients(both with CD and UC) compared to controls (IBD, p=0.007, CD, p=0.04, UC p=0.004). Prevalence of low MBL level (<500ng/mL) was significantly higher in both CD and UC groups compared to controls (p=0.002 and p=0.006). Furthermore, low MBL level was associated with isolated ileal involvement (p=0.01) and MBL deficiency (<100ng/mL) with male gender (p=0.004) in patients with CD. We failed to confirm any correlation between MBL deficiency and serum autoantibodies or NOD2/CARD15 variants.Conclusions: Our results suggest that low MBL associated with paediatric-onset IBD and ileal CD may be considered an additional marker of the IBD pathogenesis.Highlights: ► MBL levels were significantly lower in IBD than in controls. ► The prevalence of low MBL level was significantly higher in IBD than in controls. ► MBL levels in patients with CD and UC were comparable. ► Low MBL level was associated with isolated ileal involvement in CD.

Clinical status, psychosocial impairments, medical treatment and health care costs for patients with inflammatory bowel disease (IBD) in Germany: An online IBD registry - Corrected Proof

2012-04-13

Abstract: Background: The aim of this cross-sectional study was to establish an online inflammatory bowel disease (IBD) registry for a first picture of the situation of IBD outpatients' treatment in Germany.Methods: Between March 2006 and July 2007 IBD outpatients from 24 gastroenterological specialist practices and two hospitals in Germany were enrolled in an Internet-based registry to evaluate the outpatients' clinical status, psychological impairments, provided health care, as well as medical treatment and medication costs.Results: 1032 IBD patients (ulcerative colitis/UC: 519; Crohn's disease/CD: 511; indeterminate colitis: 2) were enrolled in the study (age: 43±14years/M±SD). Disease duration of all patients averaged 10±8.5years. In 519 UC-patients (49% male; 33% pancolitis), 66% were in remission as were 55% of CD patients (37 % male; 41 % active smokers). Associated with higher rates of disease activity (CDAI≥150; CAI>4) were corticosteroids (CD, UC), topical medication (UC), relevant reported depressive symptoms (15%; 6-31%) and impairments in sexuality (21%; 9-42%). Relevant medication groups prescribed were oral aminosalicylates (UC: 70%; CD: 47%); immunosuppressive therapy - mostly azathioprine/6 MP (CD: 47%; UC: 26%), and Infliximab (CD: 8%; UC: 3%).Strongly associated with their clinical disease activity in UC as well as CD patients, 15% (6–31%) reported relevant depressive symptoms and 21% (9–42%) relevant impairments in sexuality.Conclusions: The registry constitutes a large complemental database for the patient population in Germany. About one third of the IBD patients were not in clinical remission (CDAI ≥150/CAI >4) (CD: 45%; UC: 27%), although high rates of immunosuppressive drugs (CD: 47%; UC 26%) were administered. This study shows a large burden of active disease associated with an unexpectedly high (co)morbidity and high psychosocial impairments, indicating a reduced health state in IBD patients.

Schaumann bodies in Crohn's disease: a case report and review of the literature - Corrected Proof

2012-04-13

Abstract: Schaumann bodies are inclusion bodies, first described by Schaumann in 1941, typically seen in granulomatous diseases such as tuberculosis, sarcoidosis and chronic beryllium diseases. Williams WJ, in 1964, reported Schaumann bodies to occur in 10% of Crohn's disease (CD). We report a case of Crohn's disease, initially misdiagnosed as a schistosoma-related colitis for the presence of numerous calcified bodies resembling calcified ova and scattered granulomas. Subsequent biopsies showed more typical histological features and, in combination with a more complete clinical history, diagnosis of Crohn's disease was made.

Effectiveness of contrast-enhanced ultrasound for characterisation of intestinal inflammation in Crohn's disease: A comparison with surgical histopathology analysis - Corrected Proof

2012-04-09

Abstract: Background: Differentiation between predominantly inflammatory versus fibrous-predominant lesions is particularly important in order to decide the optimal therapy in patients with refractory symptoms in Crohn's disease (CD).Objective: The purpose of this investigation was to evaluate the accuracy of several US parameters, especially of contrast-enhanced US, for evaluation of mural inflammation in CD, with histopathology as the reference.Materials and methods: Preoperative ultrasound examination, including contrast-enhanced ultrasound (CEUS) was performed in 25 consecutive patients with Crohn's disease undergoing elective bowel resection. Ultrasound variables, such as wall thickness, transmural complications, colour Doppler grade, quantitative analysis of the enhancement and the presence and severity of strictures, were prospectively evaluated and compared with the histopathology results. Histopathology grading of acute inflammation using the acute inflammatory score and the degree of fibrostenosis was performed in each segment and the results were compared with all the US variables as well as with a previously defined ultrasound score system for inflammatory and fibrostenotic changes.Results: 28 segments were analysed. In pathology analysis there were 12 predominantly inflammatory segments, 9 predominantly fibrostenotic and 7 compound lesions. When the pathology score was dichotomised into two groups (inflammatory and fibrostenotic) the number of stenoses correctly classified by US was 23 out 28, with a substantial agreement (kappa=0.632). There was a good correlation between the sonographic and pathology scores, both inflammation (Spearman's, r=0.53) and fibrostenosis (Spearman's, r=0.50). Transmural complications, colour Doppler grade and percentage of increase in contrast enhancement were significantly associated with the pathology inflammatory score (p=0.018, p=0.036 and p=0.005, respectively). There was a significantly negative association between the colour Doppler grade and the pathologic fibrostenotic score.Conclusions: Ultrasound, including CEUS, can be a useful tool for distinguishing inflammatory from fibrostenotic lesions in CD. This information can be useful in the management of CD.

Adalimumab improves patient-reported outcomes and reduces indirect costs in patients with moderate to severe Crohn's disease: Results from the CARE trial - Corrected Proof

2012-04-06

Abstract: Background and aims: Crohn's disease negatively affects patients’ quality of life and ability to work. We investigated the impact of adalimumab on work productivity, daily activities, and quality of life in an open-label trial (N=945). The population comprised both infliximab-naïve and -exposed patients, including infliximab primary non-responders.Methods: Patients received adalimumab induction therapy (160mg/80mg at Weeks 0/2), followed by adalimumab 40mg every other week for up to 20weeks (patients with flares/non-response could receive 40mg weekly at/after Week 12). The Work Productivity and Activity Impairment Questionnaire and Short Inflammatory Bowel Disease Questionnaire were assessed. Indirect cost savings were estimated based on the average work productivity improvements at Week 20.Results: Mean baseline scores indicated severe productivity impairment and poor quality of life. At Week 20, 60% of infliximab-naïve and 47% of infliximab primary non-responders achieved clinically important improvements (≥9 points) on the Short Inflammatory Bowel Disease Questionnaire, and 51% and 43%, respectively, achieved the minimum clinically important difference (improvement ≥7 percentage points) for total work productivity impairment (non-responder imputation). At Week 20, 64% of infliximab-naïve and 55% of infliximab primary non-responders achieved clinically important improvements in total activity impairment. Estimated 20-week total indirect productivity-related cost savings were €3070 per infliximab-naïve patient and €2059 per infliximab-exposed patient.Conclusions: Adalimumab therapy significantly improved work productivity and disease-specific quality of life for patients with moderate to severe Crohn's disease. Patients who failed prior infliximab therapy and patients naïve to infliximab benefited from adalimumab, with potentially greater benefits for infliximab-naïve patients (NCT00409617).

Long-term outcome of tumor necrosis factor alpha antagonist's treatment in pediatric Crohn's disease - Corrected Proof

2012-04-06

Abstract: Background: Anti tumor necrosis factor alpha (TNFα) agents have become widely used in pediatric inflammatory bowel disease (IBD). So far, only few studies examined the long-term results of anti-TNFα treatment in children with IBD.Methods: The long-term outcome of pediatric patients with IBD was assessed retrospectively in a multicenter cohort of children treated with anti-TNFα beyond induction treatment. Short- and long-term response rates, predictors for loss of response, data on growth and laboratory parameters were assessed.Results: 120 patients [101 crohn's disease (CD), 19 ulcerative colitis (UC) or indeterminate colitis (IC)] received either infliximab or adalimumab. The mean age at initiation of anti-TNFα was 13.4±3.9 years and the median duration of anti-TNFα treatment was 15 months (range: 2–90). Overall, 89% of the cohort experienced short-term response following induction. Response was associated with improvement in weight and BMI Z-scores (p<0.001) but not with linear growth. Responders experienced a significant decrease in erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) during treatment (p<0.001). Albumin and hemoglobin both improved but only albumin increased significantly (p<0.001).The cumulative probability of losing response to anti-TNFα treatment was 17%, 38%, and 49% after 1, 3, and 5years, respectively. Responders had a significantly lower weight and BMI Z-scores at initiation of anti-TNFα treatment in compared to non-responders (p=0.04 and 0.02 respectively).Conclusions: Our long term cohort supports the current evidence on the effectiveness and safety of anti-TNFα treatment in children with IBD. Response to treatment was interestingly associated with lower weight and BMI.

Serum bilirubin levels and the risk of Crohn's disease - Corrected Proof

Libor Vítek — 2012-04-06

I have read with great interest a recent study by Drs. de Vries and colleagues on the association between UGT1A1 promoter gene variants and a decreased risk of Crohn's disease (CD). The authors have demonstrated that UGT1A1*28 homozygosity causing Gilbert syndrome in about 50% of carriers may protect from development of CD. In accord with the reported data on Gilbert syndrome genotype distribution among the patients with CD, the prevalence rate of homozygosity in UGT1A1*28 allele in their CD patients was substantially lower (6.27%) compared to controls (9.03%). As a limitation of the study the authors mention unavailability of serum or plasma for analysis of bilirubin levels with clinical manifestation. In this regard I would like to remind the results of our pilot study on a small cohort of CD patients (n=90) clearly demonstrating very low serum bilirubin levels with CD. In this preliminary study, each 1μmol/L increase in serum bilirubin was associated with 15% of odds for CD occurrence. We were able to confirm this data in an extended study on more than 600 CD patients, which is just being finalized for publication. Secondly, and consistent with discussed data, we demonstrated amelioration of acute chemically-induced colitis in hyperbilirubinemic Gunn rats strongly supporting protective role of bilirubin in pathogenesis of CD.

Risedronate improves bone mineral density in Crohn's disease: A complementary mechanism - Corrected Proof

Hamid Namazi — 2012-04-06

I read with great interest the paper by Soo and colleagues entitled “Risedronate improves bone mineral density in Crohn's disease: A two year randomized controlled clinical trial.” This work addressed that Risedronate can increase bone density in Crohn's disease. I would like to complete the discussion of Soo et al. by introducing a major complementary route which Risedronate could improve bone volume.

Prevalence and natural history of hepatitis B and C infections in a large population of IBD patients treated with anti-tumor necrosis factor-α agents - Corrected Proof

2012-04-05

Abstract: Background: The prevalence rates of hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients with inflammatory bowel disease (IBD) have been reported to be higher than rates of infection among the general population. Although several cases of HBV infection reactivation in IBD patients treated with anti-TNF-α agents have been described, no evidence exists that anti-TNF-α therapy exacerbates the course of HCV. The aims of this study were to assess the prevalence of HBV and HCV and the rate of HBV vaccination in a population of IBD patients; and to investigate the long-term effects of anti-TNF-α therapy in the subgroup with HBV or HCV infections.Methods: 301 patients were studied. Prior to the initiation of anti-TNF-α therapy, serum samples were tested for HBsAg and anti-HBc, anti-HBs and anti-HCV antibodies. During the follow-up, HBsAg and anti-HBc positive patients underwent periodic blood testing for viral markers, HBV-DNA and liver function; anti-HCV positive patients were assessed for liver function and HCV-RNA.Results: One patient was HBsAg positive (0.3%), and 22 (7.3%) tested positive for anti-HBc. Seventy-two patients (23.9%) had been vaccinated for HBV. Four patients tested positive for anti-HCV (1.3%). During anti-TNF-α therapy, none of the patients experienced HBV or HCV reactivation.Conclusions: HBV and HCV infection rates were similar to infection rates among the general population. Less than one quarter of the patients had been vaccinated against HBV. Anti-TNF-α agents appear to be safe for patients with HBV infection; more data are needed for patients with HCV infection.

Oral squamous cell carcinoma in a Crohn's disease patient taking azathioprine: Case report and review of the literature - Corrected Proof

2012-04-05

Abstract: Thiopurines are widely used for remission maintenance and post-operative recurrence prevention in Crohn's disease. The increased risk of cancer in transplant recipients on azathioprine is well recognized and there are concerns that this may also be true for inflammatory bowel disease patients.We report a case of a 33-year-old Caucasian woman with Crohn's disease treated with azathioprine for 9years who developed an ulcerated lesion at the right superior retromolar trigone. Biopsy specimen revealed a squamous cell carcinoma.

Serum anti-Müllerian hormone levels are lower in reproductive-age women with Crohn's disease compared to healthy control women - Corrected Proof

2012-04-03

Abstract: Background and aim: Crohn’s disease (CD) decreases fertility both directly, by inducing inflammation in the fallopian tubes and ovaries, and indirectly, through the surgical interventions and tubal adhesions associated with disease treatment. Anti-müllerian hormone (AMH) is a reliable indicator of ovarian reserve in women. We aimed to compare serum AMH levels between reproductive-age women with CD and healthy controls.Methods: Serum AMH levels were measured by ELISA in 35 women with CD and 35 age-matched healthy women controls.Results: CD patients and controls were similar in terms of age, height, weight and BMI. Mean CD duration was 60 months. CRP, ESR and leukocyte counts were significantly higher in CD patients compared to the controls (p<0.001, p=0.004 and p=0.04, respectively). AMH levels in CD patients (1.02±0.72) were significantly lower compared to the controls (1.89±1.80) (p=0.009). Serum AMH levels in CD patients with active disease (0.33±0.25) were significantly lower compared to CD patients who were in remission (1.53±0.49) (p=0.001). Serum AMH levels were similar in CD patients with a disease duration of less than 5 years (17 patients) and CD patients with a disease duration of greater than 5 years (18 patients) (p=0.8). In CD patients, a negative correlation between CDAI and serum AMH levels was found (r=-0.718, p<0.001). Serum AMH levels were similar in CD patients who had (6 patients) and had not undergone (29 patients) surgical treatment (p=0.2).Conclusion: Serum AMH levels of reproductive-age women with CD were significantly lower compared to the controls. CDAI and AMH are inversely correlated.

Tolerability of one hour 10mg/kg infliximab infusions in patients with inflammatory bowel disease - Corrected Proof

Abdenour Babouri, Anthony Buisson, Marc-André Bigard, Laurent Peyrin-Biroulet — 2012-04-03

Abstract: Background and aim: In patients with inflammatory bowel disease (IBD) tolerating 2-h infusions of 5mg/kg infliximab scheduled maintenance therapy, the infusion time can be shortened to 1-h with good tolerability. The tolerability of one 1-hour 10mg/kg infliximab infusion in patients with IBD is unknown.Methods: Between August and September 2011, 8 patients received one 1-hour 10mg/kg infliximab infusion. All patients were treated in our infusion unit under standard operating procedures. Intravenous steroid premedication was given to all patients. These 8 patients were compared to 26 IBD patients who received one 1-hour 5mg/kg infliximab infusion during the same study period at Nancy University Hospital. The charts of these 34 patients were reviewed to assess tolerability of 1-hour infliximab infusions.Results: A total of 34 patients with IBD on infliximab maintenance therapy (82.4% Crohn's disease, 17.6% ulcerative colitis; 22 females) received one 1-hour 5 or 10mg/kg infusion. Four patients were receiving concomitant immunomodulators. No severe infusions reactions were reported in the 34 IBD patients. Two mild acute reactions (7.7%) and two delayed reactions (7.7%) occurred in the 5mg/kg infliximab group. We did not observe any acute or delayed infliximab reactions in the 10mg/kg patients group.Conclusions: In patients with inflammatory bowel disease receiving infliximab scheduled maintenance therapy, 1-hour infusion time for 10mg/kg infliximab appears to be well tolerated. Large prospective studies are needed to confirm our findings.

A rare case of pericarditis, complication of infliximab treatment for Crohn's disease - Corrected Proof

Joe Devasahayam, Unnikrishnan Pillai, Alexandre Lacasse — 2012-03-30

Infliximab, a monoclonal anti-TNFα antibody, is a widely used drug in the treatment of inflammatory bowel disease. Various adverse reactions including infusion reactions, reactivation of tuberculosis, serum sickness, hematologic or bronchogenic malignancies are attributed to infliximab therapy. Pericarditis as one of the adverse reactions is very rarely reported. We present a case of pericarditis that occurred in a patient with refractory ulcerative colitis soon after initiating infliximab therapy.

TRAF3IP2 gene is associated with cutaneous extraintestinal manifestations in Inflammatory Bowel Disease - Corrected Proof

2012-03-27

Abstract: Background and aims: Genome-wide association (GWA) studies recently identified a novel gene, TRAF3IP2, involved in the susceptibility to psoriasis. Common immune-mediated mechanisms involving the skin or the gut have been suggested. We therefore aimed to assess the role of TRAF3IP2 gene in IBD, with particular regard to the development of cutaneous extraintestinal manifestations (pyoderma gangrenosum, erythema nodosum). The association with psoriasis was also assessed in a secondary analysis.Methods: The analysis included 267 Crohn's disease (CD), 200 ulcerative colitis (UC) patients and 278 healthy controls. Three TRAF3IP2 SNPs were genotyped by allelic discrimination assays. A case/control association study and a genotype/phenotype correlation analysis have been performed.Results: All three SNPs conferred a high risk to develop cutaneous manifestations in IBD. A higher risk of pyoderma gangrenosum and erythema nodosum was observed in CD patients carrying the Rs33980500 variant (OR 3.03; P=0.026). In UC, a significantly increased risk was observed for both the Rs13190932 and the Rs13196377 SNPs (OR 5.05; P=0.02 and OR 4.1; P=0.049). Moreover, association of TRAF3IP2 variants with ileal (OR=1.92), fibrostricturing (OR=1.91) and perianal CD (OR=2.03) was observed.Conclusions: This is the first preliminary report indicating that TRAF3IP2 variants increase the risk of cutaneous extraintestinal manifestations in IBD suggesting that the analysis of the TRAF3IP2 variants may be useful for identifying IBD patients at risk to develop these manifestations.

The risk of contracting pediatric inflammatory bowel disease in children with celiac disease, epilepsy, juvenile arthritis and type 1 diabetes—a nationwide study - Corrected Proof

Lauri J. Virta, Kaija-Leena Kolho — 2012-03-27

Abstract: Background and aims: The association of celiac disease with inflammatory bowel disease (IBD) in children is unclear. This study assesses the risk of IBD in children diagnosed with celiac disease and three other chronic diseases, namely epilepsy, juvenile idiopathic arthritis (JIA) and type 1 diabetes using nationwide, comprehensive registers.Methods: We identified Finnish children born between 1994 and 2008 and diagnosed with IBD (n=596) by October 2010 (aged up to 16years) in a national register of medical reimbursements, which all these patients are entitled to. The presence of other chronic diseases, such as celiac disease, epilepsy, JIA and type 1 diabetes, diagnosed before the diagnosis of IBD was accordingly identified in patients and their population-based, individually matched controls (n=2380). The data on chronic diseases are based on certificates including the diagnostic criteria. The risk of contracting IBD in children with a diagnosis of a chronic disease was analyzed using conditional logistic regression analysis.Results: Chronic diseases were more common in children contracting IBD than in their matched controls (frequency of chronic diseases 5.9% and 1.0%, respectively, p<0.001). Celiac disease associated with later development of ulcerative colitis (p<0.01) but the association with Crohn's disease was less clear (p<0.05). For the other chronic diseases, association was seen only between epilepsy and ulcerative colitis (p<0.01).Conclusion: Pediatric patients with celiac disease or epilepsy have an increased risk of developing IBD during their childhood but the risk is not high. This finding warrants a thorough investigation of intestinal symptoms in these children.

Increased titers of anti-Saccharomyces cerevisiae antibodies in Crohn's disease patients with reduced H-ficolin levels but normal MASP-2 activity - Corrected Proof

2012-03-26

Abstract: Background and aims: Mannan-binding lectin (MBL) and ficolins are microbial pattern recognition molecules that activate the lectin pathway of complement. We previously reported the association of MBL deficiency with anti-Saccharomyces cerevisiae antibodies (ASCA) in patients with Crohn's disease (CD). However, ASCA are also frequently found in MBL-proficient CD patients. Here we addressed expression/function of ficolins and MBL-associated serine protease-2 (MASP-2) regarding potential association with ASCA.Methods: ASCA titers and MBL, ficolin and MASP-2 concentrations were determined by ELISA in the serum of patients with CD, ulcerative colitis (UC), and in healthy controls. MASP-2 activity was determined by measuring complement C4b-fixation. Anti-MBL autoantibodies were detected by ELISA.Results: In CD and UC patients, L-ficolin concentrations were significantly higher compared to healthy controls (p<0.001 and p=0.029). In contrast, H-ficolin concentrations were slightly reduced in CD and UC compared to healthy controls (p=0.037 for UC vs. hc). CD patients with high ASCA titers had significantly lower H-ficolin concentrations compared to ASCA-low/negative CD patients (p=0.009). However, MASP-2 activity was not different in ASCA-negative and ASCA-positive CD patients upon both, ficolin- or MBL-mediated MASP-2 activation. Finally, anti-MBL autoantibodies were not over-represented in MBL-proficient ASCA-positive CD patients.Conclusions: Our results suggest that low expression of H-ficolin may promote elevated ASCA titers in the ASCA-positive subgroup of CD patients. However, unlike MBL deficiency, we found no evidence for low expression of serum ficolins or reduced MASP-2 activity that may predispose to ASCA development.

Reversible Henoch–Schönlein purpura complicating adalimumab therapy - Corrected Proof

Inês Marques, Ana Lagos, Jorge Reis, António Pinto, Beatriz Neves — 2012-03-23

Abstract: The tumour necrosis factor antagonists have demonstrated efficacy in the induction of remission and its maintenance in numerous chronic inflammatory conditions. These agents are generally well tolerated but with the increasing number of patients receiving anti-tumour necrosis factor-α (anti-TNFα) therapy, more adverse reactions are expected to occur. Cutaneous eruptions complicating treatment with anti-TNFα agents are common, occurring in around 20% of patients. Most reactions are mild-to-moderate and rarely warrant treatment withdrawal.We herein present a case of Henoch–Shönlein purpura (HSP) vasculitis following treatment with the monoclonal anti-TNFα antibody adalimumab for ileo-colic Crohn's disease. The reaction occurred after 18months of adalimumab therapy and discontinuation of the anti-TNFα resulted in rapid improvement of the condition. The causal relationship has become even more likely when the purpura reappeared after restarting adalimumab. The patient started infliximab, with disease control and no cutaneous side effects.To the best of our knowledge, this is the second case report of HSP complicating adalimumab therapy. Although adalimumab is theoretically less related to immune-mediated reactions, clinicians must be aware that adverse side effects may still occur. This is the first case that shows that infliximab can be safely used in patients with adalimumab related HSP. We discuss the literature and potential causal mechanisms and propose possible approaches to its management.

Infection-related hospitalizations are associated with increased mortality in patients with inflammatory bowel diseases - Corrected Proof

Ashwin N. Ananthakrishnan, Emily L. McGinley — 2012-03-22

Abstract: Introduction: Serious infections are an important side effect of immunosuppressive therapy used to treat Crohn's disease (CD) and ulcerative colitis (UC). There have been no nationally representative studies examining the spectrum of infection related hospitalizations in patients with IBD.Methods: Our study consisted of all adult CD and UC related hospitalizations from the Nationwide Inpatient Sample 2007, a national hospitalization database in the United States. We then identified all infection-related hospitalizations through codes for either the specific infections or disease processes (sepsis, pneumonia, etc.). Predictors of infections as well as the excess morbidity associated with infections were determined using multivariate regression models.Results: There were an estimated 67,221 hospitalizations related to infections in IBD patients, comprising 27.5% of all IBD hospitalizations. On multivariate analysis, infections were independently associated with age, co-morbidity, malnutrition, TPN, and bowel surgery. Infection-related hospitalizations had a four-fold greater mortality (OR 4.4, 95% CI 3.7–5.2). However, this varied by type of infection with the strongest effect seen for sepsis (OR 15.3, 95% CI 12.4–18.6), pneumonia (OR 3.6, 95% CI 2.9–4.5) and C. difficile (OR 3.2, 95% CI 2.6–4.0), and weaker effects for urinary infections (OR 1.4, 95%CI 1.1–1.7). Infections were also associated with an estimated 2.3days excess hospital stay (95% CI 2.2–2.5) and $12,482 in hospitalization charges.Conclusion: Infections account for significant morbidity and mortality in patients with IBD and disproportionately impact older IBD patients with greater co-morbidity. Pneumonia, sepsis and C difficile infection are associated with the greatest excess mortality risk.

Adalimumab for the prevention and/or treatment of post-operative recurrence of Crohn's disease: A prospective, two-year, single center, pilot study - Corrected Proof

2012-03-19

Abstract: Background: Infliximab has shown efficacy at preventing post operative recurrence (POR) of Crohn's disease (CD). This study aimed at evaluating whether adalimumab can prevent and treat POR of CD.Methods: This prospective, single-center, open-label, two-year study included 23 patients who had undergone ileocecal resection for refractory or complicated CD and were at high-risk for POR. Patients received adalimumab from post operative day 14 (Group I, n=8) or at 6months post operatively after confirmation of endoscopic recurrence (PO-ER) despite treatment with azathioprine, infliximab, or 5-ASA (patients intolerant to infliximab and azathioprine, Group II, n=15). Symptom assessment and laboratory tests were performed at monthly visits. Endoscopic findings were graded using the Rutgeerts score (RS) at 6 and 24months after initiation of adalimumab. Primary end-points were maintenance (group I) or achievement of mucosal healing (Group II). Secondary end-points were prevention of post operative clinical recurrence (PO-CR) (Group I) and endoscopic and clinical improvement (group II).Results: In Group I, PO-ER (RS≥i2) was seen in one patient at 6months PO, whereas a second patient developed PO-ER and PO-CR after 24months of treatment. In Group II, all patients had PO-ER whereas 9 (60%) patients had PO-CR at study enrolment; after 24months of treatment 9/15 (60%) patients achieved complete (RS-i0, n=3) or near complete (RS-i1, n=6) mucosal healing and 5/9 (56%) clinical remission. No serious adverse events were reported.Conclusions: This pilot study suggests that adalimumab may prevent PO-ER and treat PO-ER/CR in high risk patients for POR of CD.

Elevated levels of serum-soluble triggering receptor expressed on myeloid cells-1 in patients with IBD do not correlate with intestinal TREM-1 mRNA expression and endoscopic disease activity - Corrected Proof

2012-03-14

Abstract: Background & aims: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory responses. We have previously demonstrated a substantial increase in TREM-1-expressing macrophages in the inflamed intestinal mucosa of patients with inflammatory bowel diseases (IBD). TREM-1 is also produced as a soluble receptor (sTREM-1). Here, we aimed to determine whether serum sTREM-1 could be used as a surrogate marker of disease activity in patients with IBD.Methods: Intestinal biopsies and concurrently collected sera from patients with Crohn's disease (CD) and Ulcerative colitis (UC) enrolled in the Swiss IBD cohort study were analyzed for intestinal TREM-1 mRNA and serum sTREM-1 expression. TREM-1 mRNA and sTREM-1 were correlated with the endoscopically determined disease activity. Serum sTREM-1 and TREM-1 mRNA expression levels were further determined in sera and colonic tissues collected at various time-points post disease induction in an experimental mouse model of colitis and correlated with disease activity.Results: Expression of TREM-1 mRNA was upregulated in intestinal biopsies from patients with active disease but not in patients with quiescent disease. Serum sTREM-1 was elevated in IBD patients compared to normal controls. No substantial differences in sTREM-1 expression levels were found in patients with active versus quiescent disease. In colitic mice, colonic TREM-1 mRNA and serum sTREM-1 were also upregulated. While colonic TREM-1 mRNA expression levels correlated with disease activity, augmented serum sTREM-1 in fact associated with a milder course of disease.Conclusions: Analysis of sTREM-1 as a surrogate marker of disease activity in patients with IBD warrants caution.

Detection of CMV in pouch mucosa in a patient with acute pouchitis: The real enemy or an innocent bystander? - Corrected Proof

2012-03-14

A 30-year-old woman was diagnosed with fulminant UC in 2003 during lactation. She underwent proctocolectomy with ileal pouch–anal anastomosis due to intractable symptoms and conservative treatment failure. In August 2011, she presented with 15–20 liquid bowel movements per day accompanied with fever, abdominal tenderness and elevated laboratory markers of inflammation. A week before the onset of symptoms she reported camping holidays. A pouchoscopy revealed mild pouchitis. She was empirically treated for pouchitis with ciprofloxacin (500mg b.i.d.) and metronidazole (500mgt.i.d.). She exhibited a partial response after 72h but fever remained consistent up to 38.5°C. Stool culture turned out positive for ciprofloxacin sensitive Salmonella species. Noticeably, CMV serology revealed a positive index value with a high titer for IgG antibodies. A second pouchoscopy after 4days of treatment revealed endoscopic exacerbation. A few macrophages in the granulation tissue with features of CMV infection were identified after thorough search on the eosine and hematoxylin stained slides of multiple cut levels. (A). No CMV infected cells were found on slides immunohistochemically stained twice with antibody to CMV. CMV tissue PCR is not available in our institution. Serum PCR for CMV was negative, thus excluding primary CMV infection. The patient was kept on ciprofloxacin monotherapy without commencing anti-viral therapy. On day 7, there was a significant symptomatic improvement meaning a feverless patient with approximately 5 semiformed bowel movements per day. A third pouchoscopy 10days after admission revealed marked mucosal healing. Repeated histological examination demonstrated mild chronic inflammation consistent with resolving pouchitis without detecting any CMV infected cells (B). We concluded for a diagnosis of acute pouchitis due to Salmonella infection.

A case report: Ulcerative colitis, treatment with an antibody against tumor necrosis factor (infliximab), and subsequent liver necrosis - Corrected Proof

Urpo Kinnunen, Martti Färkkilä, Heikki Mäkisalo — 2012-03-05

Abstract: In recent years, the use of antibodies against tumor necrosis factor α (TNFα) has expanded in rheumatology, gastroenterology, and dermatology. In addition to the more common side effects such as infections and hypersensitivity reactions, elevations of liver enzymes have been reported during anti-TNFα therapy, although severe liver failure has been extremely uncommon. This report describes a patient with severe liver failure after induction therapy with the TNFα antibody infliximab (Remicade®). A 46-year old female patient received two infusions of infliximab at a dose of 400mg on weeks 0 and 8 for steroid-dependent ulcerative colitis. Eight weeks after the second infusion, she suffered acute liver failure with necrosis, requiring liver transplantation.

The efficacy of intensive granulocyte and monocyte adsorption apheresis in a patient with Crohn's disease complicated by extensive subcutaneous aseptic neutrophilic abscesses - Corrected Proof

2012-03-05

Abstract: Background and aims: Subcutaneous aseptic abscess is one phenotype of neutrophilic dermatitis. We were interested to see if a case of steroid refractory Crohn's disease (CD) complicated by subcutaneous aseptic neutrophilic abscesses responds to intensive granulocyte/monocyte adsorptive apheresis (GMA).Methods: The patient was a 21-year-old male with worsening severe CD while on oral prednisolone (30mg/day). His symptoms included fever, bloody diarrhoea and multiple painful subcutaneous nodules throughout his body. Skin biopsy showed chronic panniculitis with neutrophilic infiltrates. Further, colonoscopy showed oedematous sigmoid colon, while colonic biopsy showed non-caseous granuloma. Because biologics were feared to increase the risk of bacteraemia as the result of germ culture on his pus was not known at the time, we decided to treat this case with GMA. Five GMA sessions with the Adacolumn over 5 consecutive days (daily GMA) were initiated.Results: On admission, his CD activity index (CDAI) was 355, C-reactive protein (CRP) 11.2mg/dL. After 5 GMA sessions, CDAI decreased to 170, and CRP fell to 5.0mg/dL, with no fever. GMA was restarted at 2 sessions/week (total 10 sessions). The patient's CDAI fell to <150, and the skin lesions re-epithelialized.Conclusions: In this CD case complicated by subcutaneous aseptic neutrophilic abscesses, GMA appeared to be effective. Our impression is that when biopsy reveals neutrophil infiltrate is a major feature of the lesions, GMA should be considered. As GMA appears to have no safety concerns, a frequent GMA protocol, like daily followed by 2 to 3 times/week should be preferred over the routine weekly GMA.

Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol - Corrected Proof

2012-03-05

Abstract: Background and aims: Azathioprine and mercaptopurine remain first line immunomodulatory treatments for inflammatory bowel disease. Toxicity and non-response are significant issues. Co-prescription of allopurinol with reduced-dose (25–33%) azathioprine or mercaptopurine may overcome these problems. We present the outcome of co-prescription in a large single-centre cohort.Method: Patients on thiopurine/allopurinol co-prescription were identified. Indication for and outcome on combination treatment were established. Blood parameters and metabolite results were compared on single agent and combination treatment. Toxicity associated with combination treatment was sought.Results: 110 patients on combination treatment were identified. Clinical remission was achieved in 60/79 (76%) of patients in whom the effect of thiopurine could be studied in isolation. 20/25 patients with hepatotoxicity tolerated combination treatment and normalised their liver function tests. 24/28 patients with atypical side effects tolerated co-therapy. 13/20 non-responders responded to combination treatment. In patients started on combination treatment as first line therapy, 15/23 achieved clinical remission. Thioguanine nucleotides were significantly higher and methylated metabolites significantly lower on combination therapy. Mean cell volume was higher and total white cell and neutrophil counts lower on combination treatment. 13 adverse events occurred, including 6 specific to co-therapy (3 rash, 2 abnormal liver function tests, 1 dosing error). All were minor and self-limiting.Conclusion: This is the largest published experience of the use of allopurinol to optimise outcomes on thiopurine treatment. Combination therapy permitted successful treatment of a significant number of patients who would otherwise have been labelled as thiopurine failures. A few self-limiting side effects were encountered.

Enteroendocrine cells in terminal ileal Crohn's disease - Corrected Proof

Gordon W. Moran, Joanne Pennock, John T. McLaughlin — 2012-03-02

Abstract: Background and aims: Enteroendocrine cells sense gut luminal contents, and orchestrate digestive physiology whilst contributing to mucosal homeostasis and innate immunity. The terminal ileum is the key site of EEC expression but detailed assessment of their subtypes, lineage transcription factors and expression products has not been undertaken in terminal ileal Crohn's disease. Recent Crohn's disease gene wide association studies have linked the neuroendocrine transcription factor Phox2b; while autoantibodies to an enteroendocrine protein, ubiquitination protein 4a, have been identified as a disease behaviour biomarker.Methods: Terminal ileal tissue from small or large bowel Crohn's disease and normal controls was analysed for enteroendocrine marker expression by immunohistochemistry and quantitative polymerase chain reaction. Inflammation was graded by endoscopic, clinical, histological and biochemical scoring.Results: In small bowel disease, glucagon-like peptide 1 and chromogranin A cells were increased 2.5-fold (p=0.049) and 2-fold (p=0.031) respectively. Polypeptide YY cells were unchanged. Ileal enteroendocrine cell expression was unaffected in the presence of Crohn's colitis. Phox2b was co-localised to enteroendocrine cells and showed a 1.5-fold increase in ileal disease. Significant mRNA increases were noted for chromogranin A (3.3-fold; p=0.009), glucagon-like peptide 1 (3.1-fold; p=0.007) and ubiquitination protein 4a (2.2-fold; p=0.02). Neurogenin 3, an enteroendocrine transcription factor showed ~2 fold-upregulation (p=0.048).Conclusions: Enhanced enteroendocrine cell activity is present in small bowel disease, and observed in restricted cell lineages. This may impact on the epithelial immune response, cellular homeostasis and nutrient handling and influence appetite via increased satiety signalling in the gut-brain axis.

Histopathological characterization of cholecystectomy specimens in patients with inflammatory bowel disease - Corrected Proof

Jingmei Lin, Bo Shen, Hwa-Jeong Lee, John R. Goldblum — 2012-02-29

Abstract: Background and aims: Inflammatory bowel disease is associated with increased risk of cholelithiasis. However, the histologic patterns in gallbladders have not been extensively studied. This study is designed to characterize the histopathologic features of cholecystectomy specimens in inflammatory bowel disease patients, compared to a control group.Methods: Cholecystectomy specimens in 78 Crohn's disease patients and 50 ulcerative colitis patients were reviewed. These were compared with 93 cholecystomies from noninflammatory bowel disease patients of approximate age and sex. The pattern and extent of inflammation was noted.Results: Marked chronic cholecystitis was present in 12% of ulcerative colitis patients (P<0.05) and 10.3% of Crohn's disease patients (P>0.05), compared to 4.3% of the noninflammatory bowel disease control group. Eight percent of ulcerative colitis patients (P<0.05) and 2.6% of Crohn's disease patients (P>0.05) had acute serositis, compared to 0% of the noninflammatory bowel disease control. The third inflammatory pattern, nodular lymphoid aggregates, was significantly increased in Crohn's disease patients after adjusting for the effect of cholelithiasis. Nodular lymphoid aggregates were found in 21.2% of Crohn's disease patients and 9.7% of ulcerative colitis patients without cholelithiasis, compared to 5% of noninflammatory bowel disease controls without cholelithiasis, a statistically significant difference between the Crohn's disease and control groups (P<0.05).Conclusions: Inflammatory bowel disease patients show similar inflammatory patterns in cholecystectomy specimens compared to the general population. However, two inflammatory patterns that occur more often in ulcerative colitis patients are marked chronic cholecystitis and acute serositis, while nodular lymphoid aggregates are more common in Crohn's disease patients.

Primary tuberculous peritonitis during infliximab therapy for Crohn's disease - Corrected Proof

Ulrich Bonse-Geuking, Michael Kraus — 2012-02-29

Abstract: A 64year old male patient suffering from Crohn’s disease received infliximab therapy for a period of 5months prior to presentation to our hospital. Due to the symptoms fever, ascites, and diffuse abdominal tenderness on palpation of unknown origin, a CT scan of the abdomen was performed and led to the suspected diagnosis of a peritoneal carcinomatosis. QuantiFERON™ test revealed a tuberculosis infection and molecular analyses of a peritoneal specimen obtained by laparoscopy clearly identified Mycobacterium tuberculosis DNA. Quadruple tuberculostatic therapy was initiated and the patient's condition continuously improved thereafter.

Circulating MicroRNA in inflammatory bowel disease - Corrected Proof

2012-02-29

Abstract: Background: MicroRNAs (miRNAs) consist of a group of small noncoding RNAs that partially regulate gene expression. We investigated the expression patterns of commonly deregulated miRNAs in Crohn's disease (CD) and ulcerative colitis (UC) in peripheral blood samples of inflammatory bowel disease patients.Patients and methods: This study consisted of 128 CD and 88 UC patients, as well as 162 healthy controls. The expression patterns of the miRNA species were quantitatively assayed using reverse transcription and real-time RT-PCR. Stem-loop complementary DNAs (cDNAs) were synthesized using looped reverse transcription primers specific for each miRNA.Results: MiR-16, miR-23a, miR-29a, miR-106a, miR-107, miR-126, miR-191, miR-199a-5p, miR-200c, miR-362-3p and miR-532-3p were expressed at significantly higher levels in the blood from patients with CD compared with the healthy controls. No significant differences were observed when the CD patients were classified according to disease location and phenotype. In the UC cases three miRNAs (miR-16, miR-21, miR-28-5p, miR-151-5p, miR-155 and miR-199a-5p) were significantly increased compared to healthy controls. miR-155 was the most highly expressed of the UC-associated miRNA in blood samples.Conclusions: Our results suggest that several miRNAs could distinguish CD from UC by real-time PCR. This further highlights the putative role of miRNAs as contributors to IBD pathogenesis. They may help develop new non-invasive biomarkers to distinguish UC and CD.