P010 Precision Dosing Tool Forecasts Trough Infliximab and Associates With Disease Status in Inflammatory Bowel Diseases.

BACKGROUND: Substantial inter- and intra-individual variability of infliximab (IFX) pharmacokinetics (PK) necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). METHODS: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. RESULTS: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/ml from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming's slope = 0.90 and R2 =0.87. Observed end cycle and forecasted trough levels above 5µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7-30.2; OR = 21.0 CI95%: 3.4-127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/ml from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). CONCLUSION: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.

Quantitative relationship between infliximab exposure and inhibition of C-reactive protein synthesis to support inflammatory bowel disease management.

AIM: Quantitative and kinetic insights into the drug exposure-disease response relationship might enhance our knowledge on loss of response and support more effective monitoring of inflammatory activity by biomarkers in patients with inflammatory bowel disease (IBD) treated with infliximab (IFX). This study aimed to derive recommendations for dose adjustment and treatment optimisation based on mechanistic characterisation of the relationship between IFX serum concentration and C-reactive protein (CRP) concentration. METHODS: Data from an investigator-initiated trial included 121 patients with IBD during IFX maintenance treatment. Serum concentrations of IFX, antidrug antibodies (ADA), CRP, and disease-related covariates were determined at the mid-term and end of a dosing interval. Data were analysed using a pharmacometric nonlinear mixed-effects modelling approach. An IFX exposure-CRP model was generated and applied to evaluate dosing regimens to achieve CRP remission. RESULTS: The generated quantitative model showed that IFX has the potential to inhibit up to 72% (9% relative standard error [RSE]) of CRP synthesis in a patient. IFX concentration leading to 90% of the maximum CRP synthesis inhibition was 18.4 µg/mL (43% RSE). Presence of ADA was the most influential factor on IFX exposure. With standard dosing strategy, ≥55% of ADA+ patients experienced CRP nonremission. Shortening the dosing interval and co-therapy with immunomodulators were found to be the most beneficial strategies to maintain CRP remission. CONCLUSIONS: With the generated model we could for the first time establish a robust relationship between IFX exposure and CRP synthesis inhibition, which could be utilised for treatment optimisation in IBD patients.

Platelets Toll-like receptor-4 in Crohns disease.

BACKGROUND: Platelets are activated in Crohn's disease (CD) and interplay with leukocytes. Engagement of Toll-like receptor-4 (TLR-4), which is expressed in human platelets, may be involved in crosstalks between platelets and leukocytes leading to their mutual activation for host defense. MATERIALS AND METHODS: Human neutrophil peptides (HNPs), lipoprotein binding peptides, and sCD14 were determined by enzyme-linked immunosorbent assays in 42 patients with active CD, in 43 patients with CD in remission, and in 30 healthy individuals. Neutrophil-platelet aggregates and binding of the TLR-4 monoclonal antibody to platelets were determined by flow cytometry. RESULTS: Levels of HNPs were higher in patients with CD than in controls (P = 0.0003 vs. active CD and P = 0.01 vs. CD in remission). Likewise, neutrophils with adhering platelets were higher in patients with active CD than in controls (P = 0.004). Binding of the TLR-4 antibody in patients with active CD was similar to that in controls, while patients in remission had significantly higher binding capacities (P = 0.59 and P = 0.003). Incubation of plasma from patients with active disease or patients in remission with platelets from healthy controls confirmed lower binding of the TLR-4 antibody in the presence of plasma from active diseased patients compared to controls (P = 0.039), possibly due to high levels of lipopolysaccharides, as suggested by high levels of sCD14 and lipoprotein binding protein. CONCLUSION: Our study indicates involvement of platelet TLR-4 in enhancing the secretion of antimicrobial peptides from neutrophils. While platelet aggregation can be due to a variety of mechanisms in inflammatory disease, the mutual activation of platelets and neutrophils may augment host defense.

Early recognition of possible pitfalls in histological diagnosis of celiac disease.

OBJECTIVE: A state-of-the-art assessment of duodenal biopsies by the pathologist in the diagnosis of celiac disease (CelD) is of highest importance. However, inaccurate characterization of specific features can lead to misdiagnosis. Our hypothesis is that a detailed histological report guarantees a good quality and helps in the primary diagnostic process by preventing false-positive diagnosis of CelD. MATERIAL AND METHODS: A total of 52 patients primarily diagnosed with CelD and suspicion of misdiagnosis were selected for this retrospective study. External histological reports of duodenal biopsies were obtained and later reassessed by an experienced in-house pathologist. For an objective evaluation a histology quality score (HQS) was created. Both pathological reports were compared and causes for a possible misdiagnosis were analyzed. Diagnostic systems by Catassi and Korponay-Szabo were compared with each other. RESULTS: The original diagnosis had been confirmed in 27% by our pathologist. The HQS was significantly lower (worse) in cases where the original diagnosis were dismissed than in confirmed CelD (p = 0.018). The new diagnostic approach by Catassi and Korponay-Szabo showed a sensitivity of 89% and 83%, respectively, a specificity of 97%, a positive predictive value of 94% and a negative predictive value of 94% and 92%, respectively. CONCLUSIONS: A low quality of the histological evaluation can lead to a high probability of misdiagnosing CelD. By applying the HQS the physician can estimate whether the report is fraught with uncertainty. Ideally the score minimizes false-positive results and prevents a delay of the correct diagnosis.

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.

Model Informed Precision Dosing Tool Forecasts Trough Infliximab and Associates with Disease Status and Tumor Necrosis Factor-Alpha Levels of Inflammatory Bowel Diseases.

Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings's regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. Results: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/mL from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming's slope = 0.90 and R2 = 0.87. Observed end cycle and forecasted trough levels above 5 µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7−30.2; OR = 21.0 CI95%: 3.4−127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/mL from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). Conclusions: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.

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

BACKGROUND: IFN-γ release assays (IGRA), widely used for latent tuberculosis screening prior to anti-TNF-α treatment, are limited by indeterminate results in patients under immunomodulatory (IM) therapy. The aim of our observational study was to delineate factors associated with indeterminate IGRA results. METHODS: A total of 190 patients with inflammatory bowel disease were included. IGRA was indeterminate if the result of IFN-γ concentration was < 0·35 IU mL(-1) for tuberculosis-specific antigens and < 0·5 IU mL(-1) for the positive control. Predictors for indeterminate results were delineated from multivariate logistic regression. RESULTS: IFN-γ release assays was indeterminate in 26/190 (13·7%) patients. Indeterminate IGRA were associated with lower serum albumin levels (odds ratio [OR] 0·88, 95% confidence interval [CI] 0·79-0·96), lower absolute lymphocyte count (OR 0·39, 95% CI 0·18-0·75) and double IM therapy (OR 2·98, 95% CI 0·95-8·90). Sub-analysis of IM therapy revealed an association of steroid therapy with indeterminate IGRA (OR 3·19, 95% CI 1·35-7·70). Hypoalbuminaemia increased the risk of indeterminate IGRA by (OR 2·97, 95% CI 1·03-8·61) and lymphopaenia by (OR 3·28, 95% CI 1·41-7·65). After a mean of 18·5 ± 14·4 days, retesting of IGRA in 18 patients with indeterminate results yielded 9 negative vs. 9 indeterminate results. CONCLUSIONS: Our results reveal associations of indeterminate IGRA with low serum albumin levels and absolute lymphocyte count and double IM therapy. IGRA testing appears best to be performed prior to initiation of IM therapy in patients with inflammatory bowel disease.

Increased Induction Infliximab Clearance Predicts Early Antidrug Antibody Detection.

Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion-related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANETRA (ClinicalTrials.gov identifier: NCT01217086) and PLANETAS (NCT01220518) studies in rheumatoid arthritis and ankylosing spondylitis, respectively, to address the specified aims. Infliximab pharmacokinetics were well described by a 2-compartment model with linear mean estimated baseline clearance of 0.26 L/day. Alongside increased body weight, serum C-reactive protein, and antidrug antibody concentrations and decreased serum albumin, elevated serum glucose levels predicted higher clearance. In patients with rheumatoid arthritis, baseline infliximab clearance and body weight were the only identified predictors of early antidrug antibody detection. The odds ratio for antidrug antibody detection for each 0.1 L/day increase in baseline infliximab clearance was 1.78 (95% confidence interval, 1.50-2.12); for each 10-kg increase in body weight, this was 1.19 (1.06-1.33). Here we describe increased serum glucose levels as a novel independent predictor of baseline infliximab clearance. Estimates of baseline infliximab clearance should be incorporated to guide dosing modifications and/or antidrug antibody prophylaxis in clinical practice.

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 Crohn's 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.

Prediction of Individual Serum Infliximab Concentrations in Inflammatory Bowel Disease by a Bayesian Dashboard System.

Despite a robust exposure-response relationship of infliximab in inflammatory bowel disease (IBD), attempts to adjust dosing to individually predicted serum concentrations of infliximab (SICs) are lacking. Compared with labor-intensive conventional software for pharmacokinetic (PK) modeling (eg, NONMEM) dashboards are easy-to-use programs incorporating complex Bayesian statistics to determine individual pharmacokinetics. We evaluated various infliximab detection assays and the number of samples needed to precisely forecast individual SICs using a Bayesian dashboard. We assessed long-term infliximab retention in patients being dosed concordantly versus discordantly with Bayesian dashboard recommendations. Three hundred eighty-two serum samples from 117 adult IBD patients on infliximab maintenance therapy were analyzed by 3 commercially available assays. Data from each assay was modeled using NONMEM and a Bayesian dashboard. PK parameter precision and residual variability were assessed. Forecast concentrations from both systems were compared with observed concentrations. Infliximab retention was assessed by prediction for dose intensification via Bayesian dashboard versus real-life practice. Forecast precision of SICs varied between detection assays. At least 3 SICs from a reliable assay are needed for an accurate forecast. The Bayesian dashboard performed similarly to NONMEM to predict SICs. Patients dosed concordantly with Bayesian dashboard recommendations had a significantly longer median drug survival than those dosed discordantly (51.5 versus 4.6 months, P < .0001). The Bayesian dashboard helps to assess the diagnostic performance of infliximab detection assays. Three, not single, SICs provide sufficient information for individualized dose adjustment when incorporated into the Bayesian dashboard. Treatment adjusted to forecasted SICs is associated with longer drug retention of infliximab.

[Guidelines for vaccination of immunocompromised individuals]. / Impfungen bei Immundefekten/Immunsuppression - Expertenstatement und Empfehlungen.

Immunosuppression of various origins is associated with an increased risk of infection; therefore the prevention of infectious diseases by vaccination is especially important in immunocompromised patients. However, the response to vaccinations is often reduced in these risk groups and the application of live vaccines is contraindicated during immunosuppression.In the following expert statement, recommendations for vaccination were created on the basis of current evidence and theoretical/immunological considerations. A first, general part elaborates on efficacy and safety of vaccinations during immunosuppression, modes of action of immunosuppressive medications and recommended time intervals between immunosuppressive treatments and vaccinations. A core piece of this part is a graduation of immunosuppression into three stages, i. e. no relevant immunosuppression, mild to moderate and severe immunosuppression and the assignment of various medications (including biologicals) to one of those stages; this is followed by an overview of possible and necessary vaccinations in each of those stages.The second part gives detailed vaccination guidelines for common diseases and therapies associated with immunosuppression. Primary immune deficiencies, chronic kidney disease, diabetes mellitus, solid and hematological tumors, hematopoetic stem cell transplantation, transplantation of solid organs, aspenia, rheumatological-, gastroenterologic-, dermatologic-, neurologic diseases, biologicals during pregnancy and HIV infection are dealt with.These vaccination guidelines, compiled for the first time in Austria, aim to be of practical help for physicians to facilitate and improve vaccination coverage in immunocompromised patients and their household members and contact persons.

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 Crohn's 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.

Increased responsiveness to thrombin through protease-activated receptors (PAR)-1 and -4 in active Crohn's disease.

BACKGROUND AND AIMS: Platelets are essential in hemostasis and inflammation, thereby linking coagulation with inflammation. Abundant thrombin generation in association with inflammation is considered a major reason for the increased risk for thromboembolic events. We therefore investigated platelet responsiveness to thrombin. METHODS: In this case-control study 85 patients with Crohn's disease (active CD 42, remission 43) and 30 sex- and age-matched controls were enrolled. Clinical disease activity (Harvey-Bradshaw-Index) was assessed and CD-related data were determined by chart review. Platelets' response to protease activated receptor-1 and -4 (PAR-1, -4) was assessed by whole blood platelet aggregometry (MEA), levels of platelets adhering to monocytes (PMA), and platelet surface P-selectin. RESULTS: Platelets' aggregation after activation with the specific PAR-1 agonist (SFLLRN) and PAR-4 agonist (AYPGKF) was higher in patients with active CD compared to patients in remission and controls (p=0.0068 and p=0.0023 for SFLLRN, p=0.0019 and 0.0003 for AYPGKF). Likewise, levels of PMA after activation with PAR-1 and PAR-4 receptor agonists were higher in patients with active CD compared to patients in remission and controls (p=0.0001 and p<0.0001 for SFLLRN, p=0.0329 and p=0.0125 for AYPGKF). However, P-selectin expression on human platelets showed heterogeneous results. Only PAR-1 activation of platelets resulted in significant differences between CD patients and controls (p=0.0001 and p=0.0022 for active and inactive CD versus controls, respectively). CONCLUSIONS: Our data suggest a new mechanism of platelet activation which has the potential to increase risk for thromboembolism in patients with active CD which might be due to platelets poised for thrombin-inducible activation.

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 Crohn's 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.

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.

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-γ assay (IGRA) is part of routine management in inflammatory bowel disease (IBD) patients before starting therapy with tumor necrosis factor (TNF)-α 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-α 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%, κ = 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-α therapy appear inaccurate in patients under IM. Therefore, LTB screening might be best performed prior to initiation of IM treatment.

Prevalence and clinical impact of endoscopic pseudomembranes in patients with inflammatory bowel disease and Clostridium difficile infection.

BACKGROUND AND AIM: Limited data suggests that pseudomembranes are uncommon in patients with inflammatory bowel disease (IBD) and C. difficile associated disease (CDAD), but the reason for this is unknown. We aimed to evaluate the rate of pseudomembranes in this population, identify predictive factors for pseudomembranes' presence and assess its clinical impact. METHODS: This was a sub-study of a retrospective European Crohn's & Colitis Organization (ECCO) multi-center study on the outcome of hospitalized IBD patients with C. difficile. The present study included only patients who underwent lower endoscopy during hospitalization, and compared demographic and clinical parameters in the group of patients with discernable pseudomembranes versus those without. RESULTS: Out of 155 patients in the original cohort, 93 patients underwent lower endoscopy and constituted the study population. Endoscopic pseudomembranes were found in 12 (13%) of these patients. Patients with pseudomembranes presented more commonly with fever (p=0.02) compared to patients without pseudomembranes. No difference between the two groups was found with respect to the use of immunosuppressant drugs, background demographics or disease characteristics. Neither was there a difference between the group with or without pseudomembranes in the frequency of severe adverse clinical outcome or in the duration of hospitalization. On multi-variate analysis the presence of fever remained independently associated with the finding of pseudomembranes (OR 6, 95% CI 1.2-32, p=0.03). CONCLUSIONS: This study documents that hospitalized IBD patients with CDAD have low rate of endoscopic pseudomembranes, which is not accounted for by the use of immunosuppressant drugs. IBD patients with CDAD and discernable pseudomembranes more commonly present with fever, but their clinical outcome is similar to patients without pseudomembranes.

Imatinib mesylate inhibits autonomous erythropoiesis in patients with polycythemia vera in vitro.

The overproduction of red blood cells in patients with polycythemia vera (PV) is reflected in vitro by the formation of erythroid burst-forming units (BFU-Es) in the absence of exogenous erythropoietin. In contrast to other myeloproliferative disorders, the molecular mechanism of PV is unknown and no specific chromosomal abnormality has been described. We speculated that imatinib mesylate may reverse the pathological overproduction of red cells by inhibition of autonomous erythropoiesis. In the present study, imatinib mesylate was found to either block or strongly inhibit autonomous BFU-E formation in vitro in all patients tested. Moreover, autonomous BFU-E growth was also markedly reduced by exposure of PV cells to imatinib mesylate prior to cultivation in semisolid medium. The profound effect of imatinib mesylate on autonomous erythropoiesis suggests the involvement of an as yet unidentified kinase in the pathogenesis of PV and should provide the rationale for a forthcoming clinical trial.