Timely Monitoring of Inflammation by Fecal Lactoferrin Rapidly Predicts Therapeutic Response in Inflammatory Bowel Disease

BACKGROUND: Fecal lactoferrin (FL) levels may mirror drug-induced changes in inflammation in ulcerative colitis and Crohn disease in a timely way and could be used to assess loss of response (LOR) to biologics.METHODS: This study is a retrospective outcome review in 61 patients on adalimumab, infliximab, or vedolizumab managed in our center and followed for 6 to 24 months. Patients were 1) in clinical remission or 2) were experiencing possible LOR.RESULTS: For group 1, in 71% of 31 patients, FL slowly increased during the therapeutic interval (R2\u2005=\u20050.769; P\u2005<\u20050.001), thus reflecting increasing inflammation as drug concentrations decreased. In the remaining patients, FL was undetectable throughout the therapeutic interval because of a stronger suppression of inflammation. For group 2, in 30 patients negative for infections, FL levels measured 1 to 3 days after infusion/injection compared to preadministration values either increased (nonresponders)-in these patients the medication was switched to another class; partially decreased (partial responders)-the therapeutic interval was shortened; or were normal throughout (responders)-causes for symptoms unrelated to disease activity were found for all. After FL-based management, 3-month standardized clinical scores were normalized in both partial responders (0.58\u2005\ub1\u20050.21 vs 0.13\u2005\ub1\u20050.09; P\u2005<\u20050.001) and nonresponders (0.81\u2005\ub1\u20050.17 vs 0.12\u2005\ub1\u20050.08; P\u2005<\u20050.001), and FL levels dropped by up to 99%.CONCLUSIONS: Levels of FL reflect drug-induced changes in mucosal inflammation in a timely way, thus enabling rapid assessment of therapeutic response in patients with ulcerative colitis and with Crohn disease. In patients with suspected LOR, FL levels before and after infusion/injection accurately separated responders, partial responders, and nonresponders. The strategy proposed here is simple, accurate, and easily applicable to clinical practice

Risks of combining immunosuppressive and biological treatments in inflammatory bowel disease - in reply

We thank Roblin and Phelip for their comment on a timely issue. The recent report of the rare hepatosplenic T-cell lymphoma (HSTCL) in young patients with CD treated with both infliximab and azathioprine or steroids has rightly unleashed a series of doubts regarding the optimal use of biological agents in this and other conditions. How these observations may directly relate to the design of our study\u2014as implied by Roblin and Phelip\u2014is unclear though. While azathioprine by itself has been linked to lymphoma development including HSTCL, recent studies have shown that neither infliximab nor methotrexate, which was used in our study, alone or in combination in CD or in rheumatoid arthritis, appear to be associated with an increased risk of developing lymphomas. In addition, methotrexate alone has never been associated thus far with HSTCL in CD

Fecal lactoferrin predicts primary non-response to biologic agents in inflammatory bowel disease

3INTRODUCTION: Fecal Lactoferrin (FL) is a timely and accurate marker of inflammation in ulcerative colitis (UC) and Crohn's disease (CD). Aim of this study was to verify whether FL can predict primary non-response (PNR) to biologic agents during induction.METHODS: Retrospective outcome review in 27 patients (13 with CD and 14 with UC) tested for baseline FL and re-tested within a week after the first and second induction doses. Clinical/biochemical outcomes were evaluated at end of induction and at follow up (3-24 months).RESULTS: Compared to baseline, changes of the Harvey-Bradshaw (CD) and Partial Mayo Scoring (UC) indices at end of induction separated responders (18/27 or 67%) from non-responders (9/17 or 33%). In all patients the initial FL value at induction decreased compared to baseline, continuing to decrease after the following dose in clinical responders while bouncing back in the others. Models targeting the two consecutively decreased FL values or the second FL value compared to baseline or the second FL value compared to the first were able to accurately predict response at end of induction. Follow-up assessment confirmed clinical remission in initial responders (with FL values reduced on the average by 94±10% compared to baseline).CONCLUSIONS: In CD and UC patients during induction with biologic agents early FL measurements accurately separate clinical responders from those experiencing PNR. The method described here offers several potential advantages over other strategies to assess and manage these patients.openopenSorrentino, Dario; Nguyen, Vu Q; Love, KimSorrentino, Dario; Nguyen, Vu Q; Love, Ki

Capturing the Biologic Onset of Inflammatory Bowel Diseases: Impact on Translational and Clinical Science

While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)-both ulcerative colitis (UC) and Crohn's Disease (CD)-as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage-as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients' first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions

The Missing Link

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Development of a Dynamic Model for Diagnosis and Control of an Integrated Stack Module Based on Solid Oxide Fuel Cells

Abstract Power generation systems based on Solid Oxide Fuel Cell Systems (SOFC) are one of the most promising technology in renewable (or more efficient) energy generation thanks to low emissions, high performance, modularity and noiseless. This work aims at developing a dynamic model of an integrated system module called Diamond-A using solid oxide fuel cells. The model allows simulating the behavior of a non-conventional micro-CHP system, starting from operating variables, like temperatures or molar flows of chemical species taking part into the reactions. A lumped model approach is used to reach a good compromise between accuracy and computational time (necessary for on-board applications). Starting from detailed technical data and the system layout, the model solves a set of balance equations considering both energy flows and chemical reactions taking part in each component of the module. In the Diamond-A, the thermal exchanges among components are evaluated assuming the outlet temperature from each component as state variable. Pipes thermal losses are neglected. The entire model is generic and can be suitably applied for different layouts through the characterization of configuration model parameters. The capability of the model has been evaluated, simulating a non-conventional micro-CHP system, named HoTbox TM , under nominal operating conditions. Results are in agreement with experimental data provided in the frame of the EU project Diamond

Low dose infliximab for prevention of postoperative recurrence of crohn's disease: Long term follow-up and impact of infliximab trough levels and antibodies to infliximab

Objective In patients with postoperative recurrence of Crohn's disease endoscopic and clinical remission can be maintained for up to 1 year with low infliximab doses (3 mg/Kg). However, in theory low-dose infliximab treated patients could develop subtherapeutic trough levels, infiximab antibodies, and might loose response to therapy. To verify this hypothesis infliximab pharmacokinetics and clinical/endoscopic response were checked in a group of patients treated in the long term with low infliximab doses. Design Infliximab antibodies, infliximab levels, highly-sensitive CRP and fecal calprotectin were measured during the 8-week interval in 5 consecutive patients in clinical (Crohn's Disease Activity Index < 150) and endoscopic (Rutgeerts scores 0-1) remission after one year of therapy with infliximab 3 mg/Kg. For comparison with reported standards, infliximab pharmacokinetics and inflammatory parameters were also tested in 6 Crohn's disease patients who did not undergo surgery and who were in clinical remission while on infliximab 5 mg/ Kg. Patients on low infliximab dose also underwent colonoscopy after 18 additional months of therapy. Results Highly sensitive CRP and fecal calprotectin increased in all patients during the 8-week interval. Infliximab trough levels were lower in patients treated with the low dose compared to controls (mean\ub1SE: 2.0\ub10.3 vs 4.75\ub10.83 \uceg/mL respectively p<0.05). Infliximab antibodies were present in two of the subjects treated with low infliximab dose and in none of the controls. However, in low dose-treated patients after 18 additional months of therapy endoscopy continued to show mucosal remission and none of them developed clinical recurrence or side effects. Conclusions Patients treated with low infliximab doses had lower trough levels compared to patients treated with 5 mg/Kg and some developed antibodies to infliximab. However, low infliximab doses sustained clinical and endoscopic remission for a total of 30 months of treatment

Detailed analysis of total colectomy on health-related quality of life in adult patients with ulcerative colitis

The aim of this study was to explore the quality of life (QoL) in a group of patients who had an intractable disease on medical therapy including biologics and underwent surgery

Fecal Lactoferrin and Other Stool Markers during Normal Pregnancy and in Inflammatory Bowel Diseases: A Prospective Study and Review of the Literature

Introduction: Management of inflammatory bowel diseases (IBDs) - both Crohn's disease (CD) and ulcerative colitis (UC) - during pregnancy can be challenging since most monitoring tools available in nonpregnant patients are contraindicated.Objectives: The aim of the study was to test whether fecal inflammatory markers - specifically fecal lactoferrin - physiologically change during normal pregnancy as a prerequisite to use them to monitor IBD activity during pregnancy.Methods: Fecal lactoferrin was tested in healthy pregnant and nonpregnant women from the same geographic area and age range (18-40 years) - all negative for clinical gastrointestinal tract inflammation. A retrospective review of fecal lactoferrin levels contrasted with the Simple Endoscopic Score for CD, and the Disease Activity Index for UC was also performed in women with active IBDs within the same age range and geographical area.Results: In 30 nonpregnant subjects, fecal lactoferrin levels were 0.87 \ub1 1.08 mug/g. In 49 pregnant subjects, levels were 0.59 \ub1 0.83, 0.87 \ub1 1.13, and 0.85 \ub1 1.06 mug/g during the first, second, and third trimester, respectively (p = 0.64), with average levels for the 3 trimesters of 0.81 \ub1 1.04 mug/g (p = 0.61 compared to nonpregnant subjects). Sequential fecal lactoferrin levels (n = 26) did not differ from one trimester to the other in the individual subjects (p = 0.80). In 45 female IBD patients (27 with CD and 18 with UC), fecal lactoferrin levels were correlated with disease activity as defined by the endoscopic scores: 218, 688, and 1,175 mug/g for CD and 931, 2,088, and 2,509 mug/g for UC, respectively, for mild, moderate, and severe activity.Conclusions: Fecal lactoferrin levels during normal pregnancy are superimposable to those of nonpregnant women and significantly below levels in women of the same childbearing age with active IBDs. Additional published data - reviewed in this atricle - and our own indicate that fecal lactoferrin and other markers can be potentially used to monitor disease activity in pregnant IBD patients