Christian Primas

Factors impacting the results of interferon‐γ release assay and tuberculin skin test in routine screening for latent tuberculosis in patients with inflammatory bowel diseases

Background: Screening for latent tuberculosis (LTB) including chest x‐ray, tuberculin skin test (TST), and facultative whole blood interferon‐&ggr; assay (IGRA) is part of routine management in inflammatory bowel disease (IBD) patients before starting therapy with tumor necrosis factor (TNF)‐&agr; inhibitors. However, in patients with immunomodulators (IM) TST and IGRA might show limitations. Methods: We aimed to evaluate the results from an IGRA (QuantiFERON‐TB Gold in Tube) and TST as well as their concordance in 208 consecutive IBD patients with indications for anti‐TNF‐&agr; therapy. Associations of both tests with risk factors for LTB were determined by logistic regression. Results: During screening, 149 patients (71.6%) were under IM therapy. In 26 (12.5%) patients TST was positive, whereas 15 (7.2%) patients showed a positive result from IGRA. IGRA failed on samples from 16/208 (7.7%) patients, resulting in 192/208 (92.3%) patients in whom results from both screening tests were available. Correlation between IGRA and TST results was fair (84.9%, &kgr; = 0.21). The presence of risk factors for LTB showed association with positive results of TST (odds ratio [OR] 3.7, 1.5–9.6) and IGRA (OR 3.5, 1.2–11.3). TST was associated furthermore with age (OR 1.06, 1.02–1.10) and signs indicative of LTB in chest x‐ray (OR 4.9, 1.1–19.9). The IGRA was negatively influenced by IM therapy (OR 0.3, 0.1–0.9). Conclusion: Our study reveals that results of IGRA are negatively affected by IM therapy. Thus, current guidelines for TB screening prior anti‐TNF‐&agr; therapy appear inaccurate in patients under IM. Therefore, LTB screening might be best performed prior to initiation of IM treatment. (Inflamm Bowel Dis 2011;)

Predictors of indeterminate IFN-γ release assay in screening for latent TB in inflammatory bowel diseases

Eur J Clin Invest 2011; 41 (10): 1071–1076

Retesting for latent tuberculosis in patients with inflammatory bowel disease treated with TNF-α inhibitors

Patients treated with TNF‐α inhibitors (TNFi) are at high risk of reactivation of latent tuberculosis (LTB). Prospective studies on monitoring of TB reactivation and/or infection in this risk group are lacking.

High Risk of Transfusion-induced Alloimmunization of Patients with Inflammatory Bowel Disease

BACKGROUND Anemia is highly prevalent in inflammatory bowel disease patients, and red blood cell transfusion is often indicated already at reproductive age. Both transfusion and pregnancy may induce red cell alloantibodies, potentially complicating further transfusions and pregnancies. As recent evidence suggests that inflammation may promote red cell antibody induction, the alloimmunization risk of these patients after allogenic erythrocyte exposure was investigated. METHODS Red cell alloantibody status and clinical data were analyzed in 193 inflammatory bowel disease patients with a history of transfusion or pregnancy, and compared with transfused controls with noninflammatory diseases (n=357). RESULTS In transfused patients with inflammatory bowel disease, a 2.5-fold-increased red cell antibody prevalence was found (10/119, 8.4%), compared with transfused sex-matched controls with noninflammatory diseases (12/357, 3.4%; P=.023). Patients with inflammatory bowel disease had fewer transfusions (mean 3.0 vs 4.2, P=.003) but higher C-reactive protein levels during transfusion than controls (mean 8.4 vs 5.4 mg/dL, P <.001). The red cell antibodies of inflammatory bowel disease patients were clinically significant, directed against different Rh, Kell, Duffy, or Lutheran blood group antigens, and associated with higher number of transfusions (odds ratio 1.57; 95% confidence interval, 1.03-2.39). Conversely, immunomodulatory therapy during transfusion showed negative association (odds ratio 0.12; 95% confidence interval, 0.02-0.61). Only 1.4% of inflammatory bowel disease patients with pregnancy alone had antibodies. CONCLUSIONS Patients with inflammatory bowel disease exhibited a very high risk of transfusion-induced red cell alloimmunization, possibly potentiated by inflammation. Aside from a restrictive transfusion strategy, the implementation of prophylactic blood group phenotype matching of red cell concentrates (not only for ABO and RhD but also RhCcEe, Kell, Kidd, Duffy) could prevent antibody induction and associated complications in these patients.

The impact of intestinal resection on serum levels of anti‐Saccharomyces cerevisiae antibodies (ASCA) in patients with Crohn’s disease

Aliment Pharmacol Ther 2012; 35: 292–299

A 1-year trial of repeated high-dose intravenous iron isomaltoside 1000 to maintain stable hemoglobin levels in inflammatory bowel disease.

Abstract Objective. Iron isomaltoside 1000 (Monofer®) is a high-dose intravenous (IV) iron, which in a recent 8 weeks trial in inflammatory bowel disease (IBD) subjects with iron deficiency anemia (IDA) demonstrated good tolerability and efficacy. The present trial is an extension to this trial, which evaluates the need for additional high IV iron doses to maintain a stable hemoglobin (Hb) ≥12.0 g/dl. Material and methods. This was a prospective, open-label, 12 months trial of European IBD subjects willing to participate after completing the lead-in trial. Subjects were allowed re-dosing with 500–2000 mg single doses of iron isomaltoside 1000 infused over ∼15 min at 3 months intervals depending on a predefined algorithm. Outcome measures included Hb, safety parameters and need for additional iron dosing. Results. A total of 39 subjects were enrolled of which 34 subjects required re-dosing with a median cumulative 1-year dose of 1.8 g (mean cumulative dose 2.2 g). The mean (SD) Hb was 12.3 (1.5) g/dl at baseline, 12.8 (1.6) g/dl at 3 months, 12.8 (1.6) g/dl at 6 months, 12.9 (1.4) g/dl at 9 months and 12.9 (1.6) g/dl at 12 months. Seventy-four percent of subjects who had an Hb ≥12.0 g/dl at baseline were able to maintain Hb ≥12.0 g/dl till the end of the trial at 12 months. Nonserious probably related hypersensitivity reactions without significant hypotension were reported at the beginning of the infusion in two subjects, who recovered without sequelae. Conclusion. Repeated treatment of iron deficiency with iron isomaltoside 1000 could avoid episodes of IDA without major safety issues. Trial registration: ClinicalTrial.gov identifier: NCT01410435.

Drug monitoring of biologics in inflammatory bowel disease.

Purpose of review The monoclonal antibodies currently used for the treatment of inflammatory bowel disease (IBD) have been thoroughly studied with regard to efficacy and safety. Their pharmacokinetics and the considerable inter-individual variability of clearance and immunogenicity have attracted a great deal of attention recently. Knowledge about their properties carries the potential to optimize efficacy and durability of therapeutics that is a mainstay in the medical management of IBD. Recent findings Based on population-based pharmacokinetics models, factors impacting the clearance of infliximab have been identified, antidrug antibodies (ADA) being one of them. Trough levels have been shown to correlate with clinical response and steroid-free remission. Initial insights have recently been gained into the individual course of ADA with a potential impact on future therapeutic strategies. Summary We briefly review the current state of the literature and propose an algorithm for the use of serum trough levels and ADA as basis for monitoring of biologics in patients with IBD.

Renal insufficiency in IBD — Prevalence and possible pathogenetic aspects

BACKGROUND AND AIMS Extraintestinal manifestations of parenchymatous organs like kidney are rarely noticed in Inflammatory Bowel Disease (IBD). The aim of this study was to investigate the prevalence of renal insufficiency (RI) in IBD and look for potential causative factors and pathogenetic aspects. METHODS The study consists of two parts; the first determined the prevalence of RI in IBD and the second possible causative factors. For the first part all patients with IBD who had been investigated at our institution in the period from March 2006 to December 2007 were included. For the second part 25 IBD patients with RI were matched with 50 IBD patients without RI. To determine causative factors several gastroenterologic and renal parameters were compared between these two groups. RESULTS Eleven out of 775 patients with IBD had RI, all of them suffering from Crohns disease (CD). This led to a prevalence of 1.99% for patients with CD and of 0% for patients with ulcerative colitis (UC). Concerning IBD risk factors only duration of disease (p=0.002) and length of resected small bowel (p=0.004) had a significant impact. Two nephrologic parameters, recurrent urolithiasis and the number of interventions due to kidney stones, were risk factors for the development of RI (p=0.03). CONCLUSIONS RI is a rare (2%) but relevant complication in CD, not found in UC. Extensive small bowel resection and recurrent urolithiasis seem to be the major causative factors.

P374 Fecal transplantation in patients with moderately to severely chronic active ulcerative colitis (UC)

Background: A diminished biodiversity of the intestinal flora has been reported in patients with IBD. Restoration of a normal flora is being discussed as an alternative treatment approach. Methods: We assessed safety and efficacy of fecal transplantation (FT) in moderately to severely, chronic active patients with UC (n = 5, f/m: 2/3, median Mayo score: 11) refractory to standard therapy. Immunosuppressive therapy was stopped prior FT. Fecal donors were healthy adults with normal bowel function who were screened for enteric pathogens and serologically for viral diseases. Donor stool was diluted in saline and administered via nasojejunal tube and enema. Adverse events and blood tests were regularly obtained during a followup of 12 weeks. H2-glucose breath test was performed to exclude bacterial overgrowth at wk 4 and wk 12 weeks. Clinical activity was assessed according to Mayo Score. Results: Patients completed an antibiotic (n = 5) and probiotic (n = 4) therapy for 5 to 10 days and a single bowel lavage before FT. FT was performed daily for 3 days (n = 4). In one patient there was a gap of 5 weeks between the first and the second FT due to fever >39oC and a >8-fold increase of C-reactive protein (CRP) after first FT. Altogether, median 23.8 g (range:16.7-g-25 g) and 20 g (range: 6 g-21.7 g) stool was administered via nasojejunal tube and enema, respectively. All of the patients reported on worsening of diarrhoea and fever during FT. Additionally, a temporary increase of CRP was observed. In patients (n = 2), who had a temperature >38oC blood cultures were taken, but no bacterial pathogen was detectable. Additionally, flatulance (n = 1) and vomiting (n = 1) were reported. In the follow-up period common cold (n = 3), itchiness (n = 1), erythema (n = 1), paraesthesia on the hip (n = 1), collapse (n = 1), and blisters on the tongue (n = 1) were reported. No serious adverse event occurred. Bacterial overgrowth was not detectable in any patient. In 2 patients a further deterioration of UC was observed. Although the the general well-being improved from poor to very well at week 12 in the other 3 patients, the median total Mayo score improved only from 11 to 9. In one patient there was an improvement of the Mayo endoscopic subscore from 3 to 2. Conclusions: In our experience FT might be safe but activates a temporary systemic immune response. Our preliminary data are less impressive with regard to efficacy after a minimum follow-up of 12 weeks.

Dynamics of occurrence of refractory coeliac disease and associated complications over 25 years

Refractory coeliac disease, enteropathy associated T‐cell lymphoma and small bowel adenocarcinoma are rare but prognostically important complications in coeliac disease.