Alexander Eser

Combination immunomodulator and antibiotic treatment in patients with inflammatory bowel disease and clostridium difficile infection.

BACKGROUND & AIMS Management of Clostridium difficile infection in patients with flaring inflammatory bowel disease (IBD) has not been optimized. We investigated the effects of combination therapy with antibiotics and immunomodulators in patients with IBD and C difficile infection. METHODS We analyzed data from 155 patients (59% with ulcerative colitis [UC]) from a retrospective, European Crohns and Colitis organization, multi-center study comparing outcome of hospitalized IBD patients with C difficile infection who were treated with antibiotics (n = 51) or antibiotics and immunomodulators (n = 104). The primary composite outcome was death or colectomy within 3 months of admission, in-hospital megacolon, bowel perforation, hemodynamic shock, or respiratory failure. RESULTS The primary outcome occurred in 12% of patients given the combination treatment vs none of the patients given antibiotics alone (P = .01). UC, abdominal tenderness, or severe bloody diarrhea was more common among patients that received the combined therapy. However, multivariate analysis revealed that only the combination therapy maintained a trend for an independent association with the primary outcome (likelihood ratio = 11.9; CI, 0.9-157; P = .06). Treatment with 2 or 3 immunomodulators was correlated with the primary outcome, independent of disease severity at presentation (odds ratio [OR] = 17; CI, 3.2-91; P < .01). Acid-suppressing medications increased the risk of C difficile relapse (OR = 3.8; CI, 1.1-12.9; P = .03), whereas recent hospitalization correlated with increased rate of C difficile persistence (OR = 8; CI, 2.1-29; P = .002). CONCLUSIONS Patients with IBD that also have C difficile infection are frequently treated with a combination of antibiotics and immunomodulators. However, this combination tends to associate with a worse outcome than antibiotic therapy alone. Prospective controlled trials are urgently needed to optimize the management of these challenging patients.

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;)

Safety and Efficacy of an Oral Inhibitor of the Purinergic Receptor P2X7 in Adult Patients with Moderately to Severely Active Crohn's Disease: A Randomized Placebo-controlled, Double-blind, Phase IIa Study.

Background:AZD9056 is a selective orally active inhibitor of the purinergic receptor P2X7, which is a key player in the generation and secretion of several proinflammatory cytokines involved in the pathogenesis of Crohns disease (CD). The aim of this phase IIa study was to assess the efficacy and safety of AZD9056 for the treatment of moderately to severely active CD. Methods:We conducted a placebo-controlled, multicenter, double-blind phase IIa study in patients with moderately to severely active CD as defined by a CD Activity Index (CDAI) of at least 220. Patients were randomized in a 2:1 mode either to 200 mg of AZD9056 administered orally as a tablet once daily for 28 days or matching placebo. Primary endpoint was the change in CDAI from baseline at day 28, and secondary endpoints included clinical remission (CDAI < 150) and CDAI 70 response and improvement in the quality of life measures Short Form 36 and Inflammatory Bowel Disease Questionnaire. Changes in serum C-reactive protein and fecal calprotectin were assessed. Results:In total, 34 patients were enrolled, 24 to AZD9056 and 10 to placebo. The CDAI dropped in AZD9056-treated subjects from a baseline mean of 311 to 242 and from 262 to 239 in placebo-treated subjects (P = 0.049). Remission and response rates were numerically higher with AZD9056 versus placebo, (n = 5, 24% versus n = 1, 11%, P = 0.43 and n = 11, 52% versus n = 2, 22%, P = 0.13, respectively). Marked decrease in disease activity was observed for the CDAI subcomponents, pain and general well-being. Apart from a statistically significant improvement in the Mental Component Score of Short Form 36 for AZD9056 versus placebo (P = 0.017), no other differences in measurements of quality of life could be observed. There was no decrease in concentrations of serum C-reactive protein and fecal calprotectin during treatment. AZD9056 was well-tolerated, and no serious adverse events were reported. Conclusions:Our data suggest that the purinergic receptor P2X7 antagonist AZD9056 has the potential to improve symptoms in patients with moderate-to-severe CD combined with a beneficial risk profile. Although the lack in change of inflammatory biomarkers questions its anti-inflammatory potential, the results obtained in this study rather suggest P2X7 antagonism for the treatment of chronic abdominal pain.

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

The efficacy and safety of either infliximab or adalimumab in 362 patients with anti-TNF-α naïve Crohn's disease.

TNFα antagonists, including infliximab (IFX) and adalimumab (ADA), have revolutionised treatment for Crohns disease. Studies comparing efficacy in patients with Crohns disease naïve to TNFα antagonists are lacking.

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.