Pavol Papay

Temporal Bacterial Community Dynamics Vary Among Ulcerative Colitis Patients After Fecal Microbiota Transplantation

OBJECTIVES:Fecal microbiota transplantation (FMT) from healthy donors, which is an effective alternative for treatment of Clostridium difficile–associated disease, is being considered for several disorders such as inflammatory bowel disease, irritable bowel syndrome, and metabolic syndrome. Disease remission upon FMT is thought to be facilitated by an efficient colonization of healthy donor microbiota, but knowledge of the composition and temporal stability of patient microbiota after FMT is lacking.METHODS:Five patients with moderately to severely active ulcerative colitis (Mayo score ≥6) and refractory to standard therapy received FMT via nasojejunal tube and enema. In addition to clinical activity and adverse events, the patients’ fecal bacterial communities were monitored at multiple time points for up to 12 weeks using 16S rRNA gene-targeted pyrosequencing.RESULTS:FMT elicited fever and a temporary increase of C-reactive protein. Abundant bacteria from donors established in recipients, but the efficiency and stability of donor microbiota colonization varied greatly. A positive clinical response was observed after 12 weeks in one patient whose microbiota had been effectively augmented by FMT. This augmentation was marked by successive colonization of donor-derived phylotypes including the anti-inflammatory and/or short-chain fatty acid–producing Faecalibacterium prausnitzii, Rosebura faecis, and Bacteroides ovatus. Disease severity (as measured by the Mayo score) was associated with an overrepresentation of Enterobacteriaceae and an underrepresentation of Lachnospiraceae.CONCLUSIONS:This study highlights the value of characterizing temporally resolved microbiota dynamics for a better understanding of FMT efficacy and provides potentially useful diagnostic indicators for monitoring FMT success in the treatment of ulcerative colitis.

639 Anti-TNF Antibody-Induced Psoriasiform Skin Lesions in Patients With Inflammatory Bowel Disease Are Characterized by Interferon-y-Expressing TH1 Cells and IL-17A/IL-22-Expressing TH17 Cells and Respond to Anti-IL-12/IL-23 Antibody Treatment

Background We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor α (TNF-α) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD). Design Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab. Results Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohns disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-γ-secreting Th1 cells and IFN-α-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab. Conclusions New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions.

The First European Evidence-based Consensus on Extra-intestinal Manifestations in Inflammatory Bowel Disease.

This is the first European Crohn’s and Colitis Organisation [ECCO] consensus guideline that addresses extra-intestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. It has been drafted by 21 ECCO members from 13 European countries. Although this is the first ECCO consensus guideline that primarily addresses EIMs, it is partly derived from, updates, and replaces previous ECCO consensus advice on EIMs, contained within the consensus guidelines for Crohn’s disease1 [CD] and ulcerative colitis2 [UC]. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, topics were selected by the ECCO guidelines committee [GuiCom]. ECCO members were selected to form working groups. Provisional ECCO Statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds which included national representative participation by ECCO’s 35 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-based Medicine [www.cebm.net]. The ECCO Statements were finalised by the authors at a meeting in Vienna in October 2014 and represent consensus with agreement of at least 80% of participants. Complete consensus [100% agreement] was reached for most statements. The supporting text was then finalised under the direction of each working group leader [VA, SV, FC, MH] before being integrated by the two consensus leaders [MH, FC]. This consensus guideline is pictorially represented within the freely available ECCO e-Guide [http://www.e-guide.ecco-ibd.eu/]. Up to 50% of patients with inflammatory bowel disease [IBD] experience at least one extra-intestinal manifestation [EIM], which can present before IBD is diagnosed.34,5,6 EIMs adversely impact upon patients’ quality of life and some, such as primary sclerosing cholangitis [PSC] or venous thromboembolism [VTE], can be life-threatening. The probability of developing EIMs increases with disease duration and in patients who already have one EIM.7 …

The Impact of Thiopurines on the Risk of Surgical Recurrence in Patients With Crohn's Disease After First Intestinal Surgery

OBJECTIVES:Smoking and a lack of immunosuppressive (IS) therapy are considered risk factors for intestinal surgery in Crohns disease (CD). Good evidence for the latter is lacking. The objective of this study was to evaluate the impact of thiopurine treatment on surgical recurrence in patients after first intestinal resection for CD and its possible interaction with smoking.METHODS:Data on 326 patients after first intestinal resection were retrieved retrospectively, and subjects were grouped according to their postoperative exposure to thiopurines. Treatment with either azathioprine (AZA) or 6-mercaptopurine (6-MP) was recorded on 161 patients (49%). Smoking status was assessed by directly contacting the patients.RESULTS:Surgical recurrence occurred in 151/326 (46.3%) patients after a median time of 71 (range 3–265) months. Cox regression revealed a significant reduction of re-operation rate in patients treated with AZA/6-MP for ⩾36 months as compared with patients treated for 3–35 months, for less than 3 months, and to those without postoperative treatment with AZA/6-MP (P=0.004). Cox regression analysis revealed treatment with thiopurines for ⩾36 months (hazard ratio (HR) 0.41; 95% confidence interval (CI) 0.23–0.76, P=0.004) and smoking (HR 1.6; 95% CI 1.14–2.4, P=0.008) as independent predictors for surgical recurrence. Furthermore, longer duration of disease tended to be protective (HR 0.99; 95% CI 0.99–1.0, P=0.067).CONCLUSIONS:Long-term maintenance treatment with AZA/6-MP reduces the risk of surgical recurrence in patients with CD. We also identified smoking as a risk factor for surgical recurrence.

Optimising monitoring in the management of Crohn's disease: A physician's perspective

Management of Crohns disease has traditionally placed high value on subjective symptom assessment; however, it is increasingly appreciated that patient symptoms and objective parameters of inflammation can be disconnected. Therefore, strategies that objectively monitor inflammatory activity should be utilised throughout the disease course to optimise patient management. Initially, a thorough assessment of the severity, location and extent of disease is needed to ensure a correct diagnosis, identify any complications, help assess prognosis and select appropriate therapy. During follow-up, clinical decision-making should be driven by disease activity monitoring, with the aim of optimising treatment for tight disease control. However, few data exist to guide the choice of monitoring tools and the frequency of their use. Furthermore, adaption of monitoring strategies for symptomatic, asymptomatic and post-operative patients has not been well defined. The Annual excHangE on the ADvances in Inflammatory Bowel Disease (IBD Ahead) 2011 educational programme, which included approximately 600 gastroenterologists from 36 countries, has developed practice recommendations for the optimal monitoring of Crohns disease based on evidence and/or expert opinion. These recommendations address the need to incorporate different modalities of disease assessment (symptom and endoscopic assessment, measurement of biomarkers of inflammatory activity and cross-sectional imaging) into robust monitoring. Furthermore, the importance of measuring and recording parameters in a standardised fashion to enable longitudinal evaluation of disease activity is highlighted.

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;)

Clinical presentation of venous thromboembolism in inflammatory bowel disease.

BACKGROUND AND AIMS Patients with inflammatory bowel disease (IBD) are at increased risk of venous thromboembolism (VTE), but data on frequency, site of thrombosis and risk factors are limited. We sought to determine prevalence, incidence as well as location and clinical features of first VTE among IBD patients. METHODS We evaluated a cohort of 2811 IBD patients for a history of symptomatic, objectively confirmed first VTE, recruited from 14 referral centers. Patients with VTE before IBD diagnosis or cancer were excluded. Incidence rates were calculated based on person-years from IBD diagnosis to first VTE or end of follow-up, respectively. RESULTS 2784 patients (total observation time 24,778 person-years) were analyzed. Overall, of 157 IBD patients with a history of VTE, 142 (90.4%) had deep vein thrombosis (DVT) and/or pulmonary embolism (PE), whereas 15 (9.6%) had cerebral, portal, mesenteric, splenic or internal jugular vein thrombosis. The prevalence and incidence rate of all VTE was 5.6% and 6.3 per 1000 person years, respectively. Patients with VTE were older at IBD diagnosis than those without VTE (34.4±14.8years vs 32.1±14.4years, p=0.045), but did not differ regarding sex, underlying IBD and disease duration. 121 (77.1%) VTE were unprovoked, 122 (77.7%) occurred in outpatients and 78 (60.9%) in patients with active disease. Medication at first VTE included corticosteroids (42.3%), thiopurines (21.2%), and infliximab (0.7%). CONCLUSION VTE is frequent in IBD patients. Most of them are unprovoked and occur in outpatients. DVT and PE are most common and unusual sites of thrombosis are rare.

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

Repeat intestinal resections increase the risk of recurrence of Crohn's disease.

BACKGROUND: Which factors predict recurrence in patients with Crohn’s disease in the era of immunosuppressive medications is still under debate. OBJECTIVE: The current study was conducted to assess long-term outcome after ileocolic resection for Crohn’s disease and to define predictive factors for surgical relapse. DESIGN: This is a retrospective study. SETTINGS: The study was conducted in a tertiary referral center. PATIENTS: A consecutive cohort of patients (n = 203) with Crohn’s disease who underwent ileocolic resection between 1997 and 2006 were analyzed. The mean follow-up time was 8.4 (±2.4) years. MAIN OUTCOME MEASURES: The cumulative probability for repeated intestinal resection for recurrent Crohn’s disease was described by Kaplan-Meier curves. Predictors of surgical recurrence were analyzed by univariate tests. RESULTS: One hundred five patients (51.7%) were exposed to azathioprine/6-mercaptopurine, and 28 patients (13.8%) were exposed to tumor necrosis factor-&agr; blockers after operation. During the follow-up period, 32 patients (15.8%) were reoperated on for disease recurrence. At 5 and 10 years after index surgery, 95.5% and 81.3% of the patients had reoperation-free survival. Previous resections for Crohn’s disease (HR, 2.981; 95% CI, 1.411–6.29; p = 0.003) and urgent indication for surgery (HR, 2.729; 95% CI, 1.047–7.116; p = 0.03) were significant risk factors for reoperation. In addition, patients with postoperative complications following ileocolonic resection were more likely to require reoperation (HR, 1.712; 95% CI, 041–2.817; p = 0.03). In a multiple Cox regression model, previous intestinal resection for Crohns disease remained significant (p = 0.0114) with a HR of 2.654 (95% CI, 1.246–5.654). LIMITATIONS: The limitation is the retrospective design of the study, with its potential selection bias. CONCLUSION: In the present analysis, previous intestinal resection for Crohns disease was found to be an independent risk factor for surgical recurrence. Consequently, shorter surveillance intervals in this group of patients should be considered.

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.