Tanja Kuehbacher

Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study

Objective To evaluate the effect of different treatment strategies on enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome. Design Multicentre retrospective case-control study. Setting 23 hospitals in northern Germany. Participants 298 adults with enterohaemorrhagic E coli induced haemolytic uraemic syndrome. Main outcome measures Dialysis, seizures, mechanical ventilation, abdominal surgery owing to perforation of the bowel or bowel necrosis, and death. Results 160 of the 298 patients (54%) temporarily required dialysis, with only three needing treatment long term. 37 patients (12%) had seizures, 54 (18%) required mechanical ventilation, and 12 (4%) died. No clear benefit was found from use of plasmapheresis or plasmapheresis with glucocorticoids. 67 of the patients were treated with eculizumab, a monoclonal antibody directed against the complement cascade. No short term benefit was detected that could be attributed to this treatment. 52 patients in one centre that used a strategy of aggressive treatment with combined antibiotics had fewer seizures (2% v 15%, P=0.03), fewer deaths (0% v 5%, p=0.029), required no abdominal surgery, and excreted E coli for a shorter duration. Conclusions Enterohaemorrhagic E coli induced haemolytic uraemic syndrome is a severe self limiting acute condition. Our findings question the benefit of eculizumab and of plasmapheresis with or without glucocorticoids. Patients with established haemolytic uraemic syndrome seemed to benefit from antibiotic treatment and this should be investigated in a controlled trial.

Improvement of arthritis and arthralgia after treatment with infliximab (Remicade) in a German prospective, open-label, multicenter trial in refractory Crohn's disease.

was normal (138 10/ l). Two years later he was still positive for hepatitis B surface antigen, HBeAg, and HBV DNA measured by polymerase chain reaction; the ALT activity was elevated to 54 IU/L (normal 40). Hepatitis C virus infection and autoaggressive disorders were excluded. Physical examination revealed no deviation from normal state; there were no hematological disturbances (platelet count 149 10/ l, red blood cell [RBC] count 4.42 10/ l, white blood cell [WBC] count 4.9 10/ l). Liver ultrasound and Doppler sonography revealed no abnormalities. We decided to treat him with lamivudine at a dose of 100 mg/day (3 mg/kg/day). After a month of treatment, decline in platelets to 35 10/ l was observed. WBC and RBC counts were within normal ranges; ALT activity was 34 IU/L. Lamivudine therapy was discontinued; he received immunoglobulin for 5 days and the platelet count returned to normal (158 10/ l). During 3 months of observation after lamivudine therapy discontinuation the platelet count was in the normal range. The boy still replicated HBV (HBeAg and HBV DNA positive) and ALT activity increased to 68 IU/L. We therefore decided to administer lamivudine again at a dose of 50 mg/day. After 3 days of therapy the platelet count decreased to 55 10/ l (WBC and RBC counts were within normal ranges). Antiplatelet and antinuclear antibodies were not detected. Marrow specimens showed normal cellularity and increased megakaryocytes. The boy had recovery of platelets a week after lamivudine discontinuation without any concomitant treatment; a month later the platelet count was 137 10/ l. At this moment, to our knowledge, thrombocytopenia during lamivudine therapy has not been reported. Possible causes of cytopenia during antiviral therapy (e.g., interferon) in patients with chronic hepatitis B are mechanisms such as bone marrow suppression (7), immune-mediated toxicity of the drug (7, 8), or increased sequestration of platelets in the liver and spleen (9). We speculate that the observed thrombocytopenia in our patient treated with lamivudine could be the consequence of immune peripheral destruction of platelets, mainly in the spleen, rather than myelosuppression. The results of this study indicate that, despite confirmed lamivudine therapy safety in adults, serious adverse effects can occur, and this drug should be prescribed for children only by physicians experienced in its use, who should be cautious about the hematologically adverse effects of this drug.

Intestinal TM7 bacterial phylogenies in active inflammatory bowel disease.

TM7 is a recently described subgroup of Gram-positive uncultivable bacteria originally found in natural environmental habitats. An association of the TM7 bacterial division with the inflammatory pathogenesis of periodontitis has been previously shown. This study investigated TM7 phylogenies in patients with inflammatory bowel diseases (IBDs). The mucosal microbiota of patients with active Crohns disease (CD; n=42) and ulcerative colitis (UC; n=31) was compared with that of controls (n=33). TM7 consortia were examined using molecular techniques based on 16S rRNA genes, including clone libraries, sequencing and in situ hybridization. TM7 molecular signatures could be cloned from mucosal samples of both IBD patients and controls, but the composition of the clone libraries differed significantly. Taxonomic analysis of the sequences revealed a higher diversity of TM7 phylotypes in CD (23 different phylotypes) than in UC (10) and non-IBD controls (12). All clone libraries showed a high number of novel sequences (21 for controls, 34 for CD and 29 for UC). A highly atypical base substitution for bacterial 16S rRNA genes associated with antibiotic resistance was detected in almost all sequences from CD (97.3 %) and UC (100 %) patients compared to only 65.1 % in the controls. TM7 bacteria might play an important role in IBD similar to that previously described in oral inflammation. The alterations of TM7 bacteria and the genetically determined antibiotic resistance of TM7 species in IBD could be a relevant part of a more general alteration of bacterial microbiota in IBD as recently found, e.g. as a promoter of inflammation at early stages of disease.

Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial

BACKGROUND Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohns disease. METHODS We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohns disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohns Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (≤10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618. FINDINGS Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohns disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0·0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo. INTERPRETATION Filgotinib induced clinical remission in significantly more patients with active Crohns disease compared with placebo, and had an acceptable safety profile. FUNDING Galapagos.

mTNF reverse signalling induced by TNFα antagonists involves a GDF-1 dependent pathway: implications for Crohn's disease

Objective Mechanisms of action (MoA) of anti-tumour necrosis factor α (TNFα) therapies in Crohns disease (CD) may critically involve induction of immune cell apoptosis via membrane-bound TNFα (mTNFα) binding. Certolizumab pegol (CZP), which is effective in induction and maintenance of remission in CD lacks the ability to induce apoptosis. The aim of this study was to analyse transcriptomal responses of reverse signalling induced by the TNFα binding agents infliximab (IFX) and CZP in myelomonocytic cells. Design Induction of transcriptional patterns upon anti-TNFα stimulation was assessed using oligonucleotide microarrays. mRNA expression of GDF-1/ LASS1, which was identified as a shared target, was studied in inflammatory bowel disease by real-time PCR, while signalling pathways induced by growth and differentiation factor 1 (GDF-1) were investigated using western blots and ELISA. Results IFX and CZP induced a common signature of 20 transcripts that could be categorised into control of cell cycle, transcription activation and pre-mRNA processing. We selected GDF-1/LASS1 for functional follow-up, which was found to be upregulated in inflamed CD tissues. We show that downregulation of GDF-1/LASS1 depends on autocrine release of transforming growth factor β after mTNFα ligation. We demonstrate that GDF-1 itself acts as a novel proinflammatory factor via induction of interleukin 6 and signal transducer and activator of transcription 3 and is downregulated after IFX treatment. Conclusion Commonalities in the MoA of IFX and CZP comprise modulation of non-apoptotic pathways through downregulation of proinflammatory GDF-1. Further characterisation of the molecular role of GDF-1 in complex inflammatory processes in vivo is warranted to decide whether this proinflammatory molecule is a promising therapeutic target in patients with CD.

Influence of CYP3A4, CYP3A5, and ABCB1 Genotype and Expression on Budesonide Pharmacokinetics: A Possible Role of Intestinal CYP3A4 Expression

Budesonide treatment of chronic inflammatory bowel disease commonly leads to non‐response or adverse reactions, possibly because of alterations in efflux transport mediated by the ABCB1 gene product P‐glycoprotein or metabolism by CYP3A isoenzymes. Two groups, each consisting of nine healthy volunteers, one with the CYP3A5*1/*3 genotype (expressors) and the other with the CYP3A5*3/*3 genotype (non‐expressors), were given a single oral dose of 9 mg budesonide. Plasma and urine concentrations of budesonide and its major metabolites were determined using liquid chromatography‐tandem mass spectrometry. Subsequently, rectosigmoidal biopsies were taken for analysis of messenger RNA (mRNA) expression. Budesonide pharmacokinetics did not differ between genotype groups. However, intestinal CYP3A4 expression was shown to correlate directly with partial metabolic clearances of 16‐hydroxy‐prednisolone (r2 = 0.30; P = 0.010) and 6‐hydroxy‐budesonide (r2 = 0.25; P = 0.016), but inversely with budesonide AUC0–24 h (r2 = 0.18; P = 0.040). Interestingly, a strong correlation was found between CYP3A5 and ABCB1 expression in CYP3A5 expressors (r2 = 0.79; P = 0.001). This study suggests that intestinal CYP3A4 expression has an impact on budesonide pharmacokinetics. Moreover, CYP3A5 and ABCB1 expression appears to be coregulated.

Endoscopic ultrasound of the colon for the differentiation of Crohn's disease and ulcerative colitis in comparison with healthy controls

Diagnosis of inflammatory bowel disease (IBD) is based on clinical presentation, colonoscopy and histology. Differentiation of Crohns disease (CD) and ulcerative colitis (UC) can be difficult in some patients. Endoscopic ultrasound (EUS) provides high resolution images of the gastrointestinal wall (GI) and may be an alternative to differentiate CD/UC.

Serum Soluble IL2-Receptor is Increased in a Subpopulation of Crohns Disease Patients, Who Respond to Open Label Use of Ustekinumab, a Human Monoclonal Antibody to IL-12/23p40

for relapse of the individual patient. Results: Of the 34 patients enrolled in this trial 26 patients (14 CD, 12 UC) were evaluable for the per protocol analysis. After completion of the 12 weeks treatment phase 14 out of 26 (53.9%) patients were in remission off corticosteroids (complete responders). Another 9 (34.6%) patients were in remission at a corticosteroid dose equal or lower than their individual threshold dose (partial responders). In total, vidofludimus met the primary endpoint in 88.5% of patients (complete and partial response). Response rates did not differ between Crohns disease and ulcerative colitis. Vidofludimus was well tolerated, no drug-related serious adverse events were observed. Conclusions: This trial provides first evidence of clinical efficacy of vidofludimus in patients with Crohns disease and ulcerative colitis. Considering the favorable safety and tolerability profile vidofludimus may have potential as a novel future remission maintenance therapy in IBD. These data substantiate the relevance of IL-17 suppression in IBD as a promising and innovative therapeutic approach.

Efficacy of Filgotinib, a Selective jak1 Inhibitor, is Independent of Prior Anti-TNF Exposure: Subgroup Analysis of the Phase 2 Fitzroy Study in Moderate-To-Severe Crohn’s Disease

These three posters from the previously reported FITZROY study will be presented in the session titled “IBD: Controlled Clinical Trials in Humans” to be held on 7 May 2017 from 12:00 PM to 2:00 PM CT. As per DDW policy, the embargo on posters lifts at 9:30 AM CT on the date of presentation. The ePosters will be made available to the public after June 6 2017 at the DDW archive site, ddw.scientificposters.com.