Interaction between inflammatory bowel disease, physical activity, and myokines: Assessment of serum irisin levels.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, showed a wide spectrum of intestinal and extra-intestinal manifestations, which rendered the patients physically inactive and impaired their quality of life. It has been found that physical activity is a non-pharmacological intervention that improves the quality of life for those patients. Irisin is one member of the myokines secreted by muscle contraction during exercise and could be used as an anti-inflammatory biomarker in assessing the physical activity of IBD patients. In addition, experimental studies showed that exogenous irisin significantly decreased the inflammatory markers and the histological changes of the intestinal mucosa observed in experimental colitis. Furthermore, irisin produces changes in the diversity of the microbiota. Therefore, endogenous or exogenous irisin, via its anti-inflammatory effects, will improve the health of IBD patients and will limit the barriers to physical activity in patients with IBD.

The Usefulness of Serum Vitamin D Levels in the Assessment of IBD Activity and Response to Biologics.

The main role of vitamin D is calcium homeostasis and bone metabolism, although its activity as an immuno-modulator and its anti-inflammatory effect is well-known. Low blood vitamin D levels are common among patients with inflammatory bowel disease (IBD). Whether low vitamin D levels could affect the disease activity or it is an effect of a worse condition of the disease is still unclear. This study aimed to investigate the role of blood vitamin D levels to identify the clinical, endoscopic, and histological activity in a cohort of patients with ulcerative colitis (UC) or Crohn's disease (CD) on therapy with biological drugs. In this retrospective cohort study, 50 IBD patients (24 UC and 26 CD) that underwent colonoscopy from January 2017 to January 2020 with a concomitant serological evaluation of vitamin D were included. Patients with clinical, endoscopic, and histological activity and those who lost their clinical response to the biological drug had lower vitamin D levels compared to patients in remission or patients that did not change therapeutic regimens. A receiver operating characteristic (ROC) analysis and Youden's Index were performed to assess the optimal vitamin D levels to identify patients with the active disease. The ROC analysis showed an area under the curve (AUC) of 0.709 (p = 0.005; confidence interval (CI): 0.564-0.829), 0.769 (p < 0.001; CI: 0.628-0.876), and 0.810 (p < 0.001; CI: 0.670-0.910) for the clinical, endoscopic, and histological outcomes, respectively. The optimal vitamin D cut-off was ≤25 ng/mL. The vitamin D level is an additional useful tool in the evaluation of IBD patients with good accuracy to predict their endoscopic and histological activity and clinical response to biologics.

Prediction of treatment failure during infliximab induction therapy in inflammatory bowel disease patients based on pharmacokinetic and pharmacodynamic modeling.

BACKGROUND: In infliximab (IFX) treatment for Crohn's disease (CD) and ulcerative colitis (UC), it is difficult to predict treatment failure during the induction phase. In the present study for optimal IFX treatment, we attempted to estimate serum IFX concentration and clinical response in individual patients during the induction phase to predict the indication of therapeutic effect and the possibility of treatment failure in the maintenance phase. METHODS: We estimated pharmacokinetic and pharmacodynamic (PK/PD) parameters and predicted the serum IFX concentration and clinical response using a PK/PD model and Markov chain Monte Carlo Bayesian analysis method during the induction phase. Then, we determined whether the indication of therapeutic effect between predicted and observed clinical response were matched during the maintenance phase. RESULTS: Data obtained from 15 patients were analyzed. The correlation between predicted and observed values of serum IFX concentration (Pearson product-moment correlation coefficient, 0.700; P < 0.0001, n = 68) and clinical response of CD patients (0.790; P < 0.0001, n = 25) and UC patients (0.702; P = 0.0004, n = 21) were significantly high. The indication of therapeutic effect at the final time point of each patient (from day 115 to day 203) were successfully predicted in 14 of 15 patients (93.3%). CONCLUSIONS: This study presents prediction of serum IFX concentration and clinical response in individual patients during induction therapy, with presumption of the indication of therapeutic effect and the treatment failure in the maintenance phase. Our results show the possibility of optimizing IFX therapy during the induction phase.

Therapeutic drug monitoring of infliximab compared to standard clinical treatment with infliximab: study protocol for a randomised, controlled, open, parallel-group, phase IV study (the NOR-DRUM study).

BACKGROUND: Infliximab (INX) and other tumour necrosis factor inhibitors (TNFi) have revolutionised the treatment of several immune mediated inflammatory diseases. Still, many patients do not respond sufficiently to therapy or lose efficacy over time. The large interindividual variation in serum drug concentrations on standard doses and the development of anti-drug antibodies are thought to be major reasons for treatment failures. Therapeutic drug monitoring (TDM), an individualised treatment strategy based on systematic assessments of serum drug concentrations, has been proposed as a clinical tool to optimise efficacy of INX treatment. TDM seems reasonable both from a clinical and an economical point of view, but the effectiveness of this treatment strategy has not yet been demonstrated in randomised clinical trials. The NORwegian DRUg Monitoring study (NOR-DRUM) aims to assess the effectiveness of TDM, both with regard to the achievement of remission in patients starting INX treatment (part A) as well as to maintain disease control in patients on INX treatment (part B). METHODS: The NOR-DRUM study is a randomised, open, controlled, parallel-group, comparative, multi-centre, national, superiority, phase IV study with two separate parts, NOR-DRUM A and NOR-DRUM B. Patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, ulcerative colitis, Crohn's disease and psoriasis are included. In both study parts participants are randomised 1:1 to either TDM of infliximab (intervention group) or to standard treatment with infliximab without knowledge of drug levels or ADAb status (control group). NOR-DRUM A will include 400 patients starting INX therapy. The primary outcome is remission at 30 weeks. In NOR-DRUM B, 450 patients on maintenance treatment with INX will be included. The primary endpoint is occurrence of disease worsening during the 52-week study period. DISCUSSION: As the first trial to assess the effectiveness, safety and cost-effectiveness of TDM in patients receiving TNFi for a range of immune mediated inflammatory diseases, we hope that the NOR-DRUM study will contribute to the advancement of evidence based personalised treatment with biological medicines. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03074656. Registered on 090317.

Endoscopic score vs blood cell indices for determining timing of immunomodulator withdrawal in quiescent ulcerative colitis.

While immunomodulators (IMs) are used as key drugs in remission maintenance treatment for ulcerative colitis (UC), there has been no evidence to date for determining monitoring methods and drug withdrawal. Therefore, we examined if a decrease in white blood cell count (WBC) and an elevation in mean cell volume (MCV) could be used as optimization indices and if mucosal healing (MH) could be a rationale for determining the time of IM withdrawal. Subjects were 89 UC patients who were using IMs and for whom clinical remission had been maintained. Those with a Rachmilewitz Clinical Activity Index score of 4 or lower and those with a Mayo endoscopic subscore (MES) of 0 or 1 were defined as MH. The remission maintenance rates of the following comparative groups were examined: an IM continuation group and an IM withdrawal group; an IM continuation group with a WBC of less than 3000 or a MCV of 100 or greater and an IM continuation group with a WBC of 3000 or greater and a MCV of 99 or lower; an IM continuation group of patients for whom MH had been achieved and an IM continuation group of patients for whom MH had not been achieved; and an IM withdrawal group with a MES of 0 and an IM withdrawal group with a MES of 1. A significantly higher remission maintenance rate was observed in the IM continuation group compared to the withdrawal group (p < 0.01). No significant difference was observed between the IM continuation group with a WBC of less than 3000 or a MCV of 100 or greater and the IM continuation group with a WBC of 3000 or greater and a MCV of 99 or lower (p = 0.08). Higher remission maintenance rates were observed in the IM continuation group of patients for whom MH had been achieved compared to the IM continuation group of patients for whom MH had not been achieved (p = 0.03). No significant difference was observed between the IM withdrawal group with MES 0 and the IM withdrawal group with MES 1. (p = 0.48). This retrospective study showed that remission maintenance could be firmly obtained by continuing IM administration in case of endoscopic MH; however, MH was not an indicator of IM withdrawal.

Prediction of treatment outcome and relapse in inflammatory bowel disease.

INTRODUCTION: Prediction of treatment outcome and clinical relapse in patients with inflammatory bowel disease (IBD), either ulcerative colitis (UC) or Crohn's disease (CD), is particularly important because therapeutics for IBD are not always effective and patients in remission could frequently relapse. Because undergoing endoscopy for the purpose is sometimes invasive and burdensome to patients, the performance of surrogate biomarkers has been investigated. Areas covered: We particularly featured the performance of patient symptoms, blood markers including C-reactive protein (CRP), fecal markers including fecal calprotectin (Fcal) and fecal immunochemical test (FIT) for prediction of endoscopic mucosal healing (MH) and prediction of relapse. Studies of other modalities and therapeutic drug monitoring (TDM) have also been explored. Expert opinion: Meticulous evaluation of patient symptoms could be predictive for MH in UC. CRP and Fcal may be accurate in prediction of MH of CD when MH is evaluated throughout the entire intestine including the small bowel. Repeated measurements of fecal markers including Fcal and FIT in patients with clinical remission would raise predictability of relapse. Prediction of treatment outcome by monitoring with blood markers including CRP, fecal markers including Fcal, and TDM has frequently been performed in recent clinical trials and shown to be effective.

Detection of anti-infliximab antibodies in Slovak IBD patients and its costs saving effect.

OBJECTIVE: Management chronic inflammatory bowel disease (IBD) patients is associated with diagnosis, targeted treatment and and individual approach. There is a group of patients which loss the response to the biologic treatment caused by insufficient levels of biologics or positive antibodies against these drugs. This study was aimed to determine the prevalence of patients with positive antibodies against the biological treatment and the costs saving probabilities of the antibodies detection during the treatment. STUDY DESIGN: This retrospective study was based on examination of 183 IBD patients' sera (72 with Crohn's disease (CD) and 111 ulcerative colitis (UC)) treated with infiliximab. METHODS: Circulating serum infliximab concentrations and anti-infliximab antibodies (ATI) were quantified by ELISA methods. Costs associated with the treatment were analysed from the data of General Health Insurance Company, Slovakia. RESULTS: The average infliximab concentrations in groups of CD were 2.9 µg/mL, 38.9% of samples had a concentration ≤1 µg/mL. Group with UC had average infliximab levels of 3.19 µg/mL, 32.4% bellow ≤1 µg/mL. Positive ATI levels were detected in 52 patients, in 28 patients with CD (38.8%) and 24 patients with UC (21.6%). The average values of the antibodies were 387.75 U/ml in CD and 391.94 U/ml in UC group. More than 28% IBD patients were positive for ATI. After application of the results to the database of all IBD patients, finishing of the treatment with ATI could lead (after considering the ATI quantification costs) to possible annual savings of more than €2 million in Slovakian health-care system. CONCLUSIONS: Monitoring of infliximab and antibodies against infliximab and anti-TNF-α biologics may help optimize treatment strategies and costs for biological treatment.

Use of Reticulocyte Hemoglobin Content in the Assessment of Iron Deficiency in Children With Inflammatory Bowel Disease.

BACKGROUND: Iron deficiency and anemia affect up to 50% to 75% of patients with inflammatory bowel disease (IBD). Iron deficiency in IBD may be difficult to diagnose because of the effect of inflammation on iron status biomarkers. Thus, there is a need for better methods to accurately determine iron status in IBD. OBJECTIVE: The aim of the study was to investigate the association of inflammation with hemoglobin content of reticulocytes (CHr) and the utility of CHr in comparison to standard iron biomarkers. METHODS: We conducted a cross-sectional study of children with IBD. Iron biomarkers (CHr, ferritin, soluble transferrin receptor [sTfR], hepcidin, hemoglobin) were measured along with systemic biomarkers of inflammation (C-reactive protein, α1-acid glycoprotein]. Spearman correlations were used to evaluate the relation of inflammation and iron biomarkers. The criterion standard for iron deficiency was defined as inflammation-corrected ferritin <15 µg/L or sTfR >8.3 mg/L. Receiver operating characteristic curves were used to estimate the prognostic values of all iron biomarkers to identify patients with iron deficiency. RESULTS: We analyzed data in 62 children ages 5 to 18 years. Sixty-nine percent of our subjects had Crohn disease and 31% had ulcerative colitis, of which 42% were girls and 53% African American. The prevalence of anemia was 32%, of iron deficiency was 52% using ferritin <15 µg/L or sTfR >8.3 mg/L, 39% using red blood cell distribution width of >14.5%, 26% using body iron stores of <0 mg/kg body weight, 25% using CHr of <28 pg, and 11% using mean corpuscular volume of <75 fL/cell. The prevalence of elevated CRP or AGP was 48%. After correcting ferritin and sTfR levels for inflammation, the prevalence of iron deficiency was 68%. CHr was correlated with C-reactive protein (rs -0.44, P < 0.001) and α1-acid glycoprotein (rs -0.37, P < 0.05). The optimal prognostic value for inflammation-adjusted CHr to predict iron deficiency was 34 pg (area under the receiver operating characteristic of 0.70), with 88% sensitivity and 30% specificity. CONCLUSIONS: Iron deficiency and anemia are common in this pediatric IBD cohort. All explored iron biomarkers, including CHr, were affected by inflammation and should be adjusted. A single iron biomarker is unlikely to best predict iron deficiency in pediatric IBD. Iron intervention studies are needed to examine the response of iron biomarkers to iron supplementation in the setting of inflammation.

Assessment of Circulating MicroRNAs for the Diagnosis and Disease Activity Evaluation in Patients with Ulcerative Colitis by Using the Nanostring Technology.

BACKGROUND: Clinical decision and patient care management in inflammatory bowel diseases is largely based on the assessment of clinical symptoms, while the biomarkers currently in use poorly reflect the actual disease activity. Therefore, the identification of novel biomarkers will serve an unmet clinical need for IBD screening and patient management. We examined the utility of circulating microRNAs for diagnosis and disease activity monitoring in patients with ulcerative colitis (UC). METHODS: Blood serum microRNAs were isolated from patients with UC with active and inactive disease and healthy donors. High-throughput microRNA profiling was performed using the Nanostring technology platform. Clinical disease activity was captured by calculating the partial Mayo score. C-reactive protein was measured in patients with UC as part of their clinical monitoring. The profiles of circulating microRNAs and C-reactive protein were correlated with clinical disease indices. RESULTS: We have identified a signature of 12 circulating microRNAs that differentiate patients with UC from control subjects. Moreover, 6 of these microRNAs significantly correlated with UC disease activity. Importantly, a set of 4 microRNAs (hsa-miR-4454, hsa-miR-223-3p, hsa-miR-23a-3p, and hsa-miR-320e), which correlated with UC disease activity were found to have higher sensitivity and specificity values than C-reactive protein. CONCLUSIONS: Circulating microRNAs provide a novel diagnostic and prognostic marker for patients with UC. The use of an FDA-approved platform could accelerate the application of microRNA screening in a gastrointenstinal clinical setting. When used in combination with current diagnostic and disease activity assessment modalities, microRNAs could improve both IBD screening and care management.

Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease.

BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC. METHODS: We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 µg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase. RESULTS: At screening, 115 of 263 patients had a TC of infliximab of 3-7 µg/mL (43.7%). Of 76 patients with TCs <3 µg/mL, 69 patients (91%) achieved TCs of 3-7 µg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 µg/mL, 67 patients (93%) achieved TCs of 3-7 µg/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction (P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point (P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P = .018). CONCLUSIONS: Targeting patients' infliximab TCs to 3-7 µg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38.

Acesso ao cuidado à saúde da criança em serviços de atenção primária / Access to child's health care in primary care services / Acceso al cuidado de la salud del niño en servicios de atención primaria

Realizou-se uma pesquisa de abordagem qualitativa com base no referencial metodológico da hermenêutica dialética, com o objetivo de identificar o atributo acesso da atenção primária para a resolução dos problemas de saúde de crianças menores de um ano a partir dos relatos de pais e cuidadores. Envolveram-se 16 cuidadores de crianças atendidas em unidades de pronto atendimento de Cascavel-PR, em 2010. Foram reconhecidas quatro categorias temáticas: Aconselhamento familiar ao buscar atenção à saúde da criança; Ausência de acolhimento ao primeiro contato; Presença de classificação de risco para atenção à saúde da criança; Barreiras que impedem o acesso à atenção à saúde. Concluiu-se que as famílias exibiram dificuldades para alcançar resolutividade aos problemas de saúde dos filhos, mediante a falta de acesso aos serviços de atenção primária.

It was conducted a qualitative study based on the methodological framework of dialectical hermeneutics, aiming to identify the attribute access from primary care to solve the health problems of children under one year old from the reports of parents and caregivers. Sixteen caregivers of children were involved, all of them seen in the emergency units of Cascavel-PR, in 2010. Four thematic categories were recognized: Family counselling in seeking health care for the child; Absence of reception on the first contact; Presence of risk classification to the child´s health attention; Barriers that block the access to health care. It was conclude that, families showed difficulties to reach the solution for their children´s health, because of the lack of access to primary care services.

Llevó-se a cabo un estudio cualitativo basado en el marco metodológico de la hermenéutica dialéctica, con el objetivo de identificar el atributo de acceso a la atención primaria para resolver los problemas de salud de los niños menores de un año, a partir de los informes de los padres y cuidadores. Se involucró 16 cuidadores de niños atendidos en las unidades de emergencia de Cascavel-PR, en 2010. Cuatro categorías temáticas fueron reconocidas: Asesoramiento de la familia en la búsqueda de atención de salud para el niño; Ausencia de acogimiento al primero contacto; Presencia de clasificación de riesgo para el cuidado de la salud del niño; Barreras que impiden el acceso a la atención sanitaria. Se concluyó que las familias tuvieron dificultades para lograr la solución de los problemas de salud de los niños, mediante la falta de acceso a los servicios de atención primaria.

Treating inflammatory bowel disease by adsorptive leucocytapheresis: a desire to treat without drugs.

Ulcerative colitis and Crohn's disease are the major phenotypes of the idiopathic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms, impairing function and quality of life. Current medications are aimed at reducing the symptoms or suppressing exacerbations. However, patients require life-long medications, and this can lead to drug dependency, loss of response together with adverse side effects. Indeed, drug side effects become additional morbidity factor in many patients on long-term medications. Nonetheless, the efficacy of anti-tumour necrosis factors (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation of IBD. However, inflammatory cytokines are released by patients' own cellular elements including myeloid lineage leucocytes, which in patients with IBD are elevated with activation behaviour and prolonged survival. Accordingly, these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn. Based on this background, recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries. Efficacy rates have been impressive as well as disappointing. In fact the clinical response to GMA seems to define the patients' disease course, response to medications, duration of active disease, and severity at entry. The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active disease prior to GMA. Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA. It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD. Additionally, GMA is very much favoured by patients for its good safety profile. GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates. However, in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines and achieve disease remission. The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond to GMA and avoid pharmacologics. This should fulfill the desire to treat without drugs.

Biomarkers in inflammatory bowel diseases: current status and proteomics identification strategies.

Unambiguous diagnosis of the two main forms of inflammatory bowel diseases (IBD): Ulcerative colitis (UC) and Crohn's disease (CD), represents a challenge in the early stages of the diseases. The diagnosis may be established several years after the debut of symptoms. Hence, protein biomarkers for early and accurate diagnostic could help clinicians improve treatment of the individual patients. Moreover, the biomarkers could aid physicians to predict disease courses and in this way, identify patients in need of intensive treatment. Patients with low risk of disease flares may avoid treatment with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine or stool later can be screened for. When considering the protein complexity encountered in intestinal biopsy-samples and the recent development within the field of mass spectrometry driven quantitative proteomics, a more thorough and accurate biomarker discovery endeavor could today be performed than ever before. In this review, we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing novel biomarkers, as well as suggesting future targets for analysis.

A novel gas chromatography mass spectrometry-based serum diagnostic and assessment approach to ulcerative colitis.

BACKGROUND & AIMS: To improve the clinical course of ulcerative colitis (UC), more accurate serum diagnostic and assessment methods are required. We used serum metabolomics to develop diagnostic and assessment methods for UC. METHODS: Sera from UC patients, Crohn's disease (CD) patients, and healthy volunteers (HV) were collected at multiple institutions. The UC and HV were randomly allocated to the training or validation set, and their serum metabolites were analyzed by gas chromatography mass spectrometry (GC/MS). Using the training set, diagnostic and assessment models for UC were established by multiple logistic regression analysis. Then, the models were assessed using the validation set. Additionally, to establish a diagnostic model for discriminating UC from CD, the CD patients' data were used. RESULTS: The diagnostic model for discriminating UC from HV demonstrated an AUC of 0.988, 93.33% sensitivity, and 95.00% specificity in the training set and 95.00% sensitivity and 98.33% specificity in the validation set. Another model for discriminating UC from CD exhibited an AUC of 0.965, 85.00% sensitivity, and 97.44% specificity in the training set and 83.33% sensitivity in the validation set. The model for assessing UC showed an AUC of 0.967, 84.62% sensitivity, and 88.23% specificity in the training set and 84.62% sensitivity, 91.18% specificity, and a significant correlation with the clinical activity index (rs=0.7371, P<0.0001) in the validation set. CONCLUSIONS: Our models demonstrated high performance and might lead to the development of a novel treatment selection method based on UC condition.

High burden of iron deficiency and different types of anemia in inflammatory bowel disease outpatients in Scandinavia: a longitudinal 2-year follow-up study.

OBJECTIVE: The prevalence of anemia in inflammatory bowel disease (IBD) has been broadly described. The recurrence, type and burden of anemia remain unenlightened. The primary objective was to describe this. The secondary objective was to evaluate the implementation of European guidelines. MATERIALS AND METHODS: This longitudinal follow-up study included 300 IBD outpatients from six centers in Scandinavia. Patients were enrolled in a research cohort, in which each center included 5% of their IBD cohort. The study was prospectively planned, while data were retrospectively collected. The burden of anemia was calculated as number of months with anemia. A Markov model was used to calculate the probabilities of transitioning between stages. The European guidelines were used as the standard for anemia management. RESULTS: Anemia affected > 50% of IBD outpatients during the 2-year observation period. Totally, 20% of the total observation time was spent in anemia. Over the 7200 months of observation, anemia was found in 1410 months. The most frequent type was combined anemia (63%). Combined anemia covers both anemia of chronic disease (ACD) and iron-deficiency anemia (IDA). Pure ACD was present in 21% of burden time, while pure IDA was present in 16% of burden time. The European guidelines have mainly been implemented. CONCLUSION: Anemia affected a majority of the IBD outpatients. One in five months, the patients were anemic. Anemia related to inflammation dominated the different types of anemia. Pure IDA was found in for 16%. These findings, despite a fair implementation of guidelines.

Assessment of neutrophil-lymphocyte ratio in ulcerative colitis: a promising marker in predicting disease severity.

BACKGROUND AND AIM: In order to diagnosis and monitor the disease activity of ulcerative colitis (UC), serum biomarkers are generally used, but none of them are specific for intestinal inflammation. It is therefore desirable in clinical practice to be able to assess disease activity with simple, inexpensive and objective tools. The objective of the present study was to assess whether the neutrophil-lymphocyte ratio (NLR) would be useful in predicting disease severity in UC patients who had not received corticosteroid or immunosuppressive drugs within a defined period of time. Additionally, a possible relationship of NLR with other inflammatory markers in UC patients was also investigated. METHODS: We designed a retrospective study examining the utility of NLR in estimating disease severity in UC patients admitted to our hospital between 2008 and 2011. In total, 119 patients with active UC and 77 patients with inactive UC were enrolled in the study group, and 59 age and gender matched healthy subjects were included as the control group. Disease activity was assessed using Truelove and Witts criteria. RESULTS: In the active UC group, NLR values were found to be elevated compared to inactive UC patients and controls (3.22 ± 1.29, 1.84 ± 0.69 and 2.01 ± 0.64, respectively). Using ROC statistics, a cut-off value of 2.16 indicated the presence of active disease with a sensitivity of 81.8% and a specificity of 80.5% (positive predictive value [PPV] 86.8%, negative predictive value [NPV] 73.8%). NLR values were found to be correlated with WBC and ESR levels. CONCLUSIONS: The present study revealed that NLR is increased in active UC. Peripheral blood NLR can reflect disease activity and can be used as an additional marker for estimating intestinal inflammation.

Novel, objective, multivariate biomarkers composed of plasma amino acid profiles for the diagnosis and assessment of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic intestinal disorder that is associated with a limited number of clinical biomarkers. In order to facilitate the diagnosis of IBD and assess its disease activity, we investigated the potential of novel multivariate indexes using statistical modeling of plasma amino acid concentrations (aminogram). METHODOLOGY AND PRINCIPAL FINDINGS: We measured fasting plasma aminograms in 387 IBD patients (Crohn's disease (CD), n = 165; ulcerative colitis (UC), n = 222) and 210 healthy controls. Based on Fisher linear classifiers, multivariate indexes were developed from the aminogram in discovery samples (CD, n = 102; UC, n = 102; age and sex-matched healthy controls, n = 102) and internally validated. The indexes were used to discriminate between CD or UC patients and healthy controls, as well as between patients with active disease and those in remission. We assessed index performances using the area under the curve of the receiver operating characteristic (ROC AUC). We observed significant alterations to the plasma aminogram, including histidine and tryptophan. The multivariate indexes established from plasma aminograms were able to distinguish CD or UC patients from healthy controls with ROC AUCs of 0.940 (95% confidence interval (CI): 0.898-0.983) and 0.894 (95%CI: 0.853-0.935), respectively in validation samples (CD, n = 63; UC, n = 120; healthy controls, n = 108). In addition, other indexes appeared to be a measure of disease activity. These indexes distinguished active CD or UC patients from each remission patients with ROC AUCs of 0.894 (95%CI: 0.853-0.935) and 0.849 (95%CI: 0.770-0.928), and correlated with clinical disease activity indexes for CD (r(s) = 0.592, 95%CI: 0.385-0.742, p<0.001) or UC (r(s) = 0.598, 95%CI: 0.452-0.713, p<0.001), respectively. CONCLUSIONS AND SIGNIFICANCE: In this study, we demonstrated that established multivariate indexes composed of plasma amino acid profiles can serve as novel, non-invasive, objective biomarkers for the diagnosis and monitoring of IBD, providing us with new insights into the pathophysiology of the disease.

Role of serum cytokine profile in ulcerative colitis assessment.

BACKGROUND: Several cytokines are overexpressed in the colonic mucosa of patients with ulcerative colitis (UC). The measurement of these parameters in plasma could be useful in diagnosis and disease assessment. METHODS: In all, 67 UC patients and 21 healthy controls were enrolled. At inclusion, clinical, endoscopic, and histological disease activity were assessed using the Ulcerative Colitis Activity Index (UCAI) and the Baron and Geboes scales, respectively. Serum cytokine concentrations were analyzed with a multiplex system (Bio-Plex pro, Bio-Rad) measuring interleukin (IL)-1-ß, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17, interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α). Multiple logistic regression was used to design a serum cytokines profile. RESULTS: In the UC group the disease activity was moderate to severe based on clinical evaluation in 35 patients (52.2%), by endoscopic appearance in 45 (67.2%), and in 53 patients (81.6%) using histology. With respect to controls, the multivariate analysis identified that UC patients had higher IL-8 (odds ratio [OR] = 1.37; P = 0.002) and IL-10 concentrations (OR = 3.88; P = 0.012) with lower levels of IFN-γ (OR = 0.95; P = 0.002). The model had an accuracy of 77.3%, which increased to 94.6% when only newly diagnosed patients were considered. Patients with moderate to severe disease according to their clinical score showed a higher concentration of IL-8 (OR = 1.16; P = 0.012) and IL-10 (OR = 1.76; P = 0.039) with lower levels of IL-17 (OR = 0.97; P = 0.021). The IL-8 serum concentration was also related to endoscopic and histological severity (OR = 1.10; P = 0.026 and OR = 1.33, P = 0.017, respectively). CONCLUSIONS: A serum cytokine profile may be an auxiliary tool for the diagnosis and severity assessment of UC. IL-8 seems to be a reliable biomarker, closely related to disease activity.

Vitamin D status in veterans with inflammatory bowel disease: relationship to health care costs and services.

Vitamin D deficiency is a global pandemic associated with increased health care costs and could play a role in the pathogenesis and management of inflammatory bowel disease. This study examined vitamin D status in veterans with ulcerative colitis (UC) and Crohn's disease (CD) and assessed its relationship to health care costs and service utilization. Veteran patients (n = 125) with UC or CD and with an available 25-hydroxyvitamin D level were studied. CD patients were more likely to be vitamin D insufficient than the UC group. Despite the higher vitamin D levels among UC patients, they were significantly more likely to utilize laboratory and pharmacy services compared with CD patients, whereas patients with CD had significantly higher radiology and pharmacy costs. Thus, it is likely that disease-specific characteristics rather than vitamin D status determine the costs of health care services in veterans with established inflammatory bowel disease.

Assessment of the influence of the inflammatory process on the activation of blood platelets and morphological parameters in patients with ulcerative colitis (colitis ulcerosa).

Ulcerative colitis (colitis ulcerosa) is a non-specific inflammatory bowel disease of unknown etiology. The symptoms which are observed in the course of ulcerative colitis are: an increase in the number of leukocytes and blood platelets, an increase in the concentration of IL-6 and anemia. Blood platelets are the key element, linking the processes of hemostasis, inflammation and the repair of damaged tissues. Activation of blood platelets is connected with changes in their shape and the occurrence of the reaction of release. P-selectin appears on the surfaces of activated blood platelets and the concentration level of soluble P-selectin increases in the blood plasma. The aim of this study was to define whether the increased number of blood platelets in patients with ulcerative colitis accompanies changes in their activation and morphology. A total of 16 subjects with ulcerative colitis and 32 healthy subjects were studied. Mean platelet count, morphological parameters of platelets and MPC were measured using an ADVIA 120 hematology analyzer. Concentrations of sP-selectin and IL-6 in serum were marked by immunoassay (ELISA). MPC, concentration of sP-selectin and IL-6 were significantly higher in subjects with ulcerative colitis compared to those in the healthy group. There was a decrease of MPV in patients with ulcerative colitis, which is statistically significant. Chronic inflammation in patients with ulcerative colitis causes an increase in the number of blood platelets, a change in their morphology and activation. Decreased MPV value reflects activation and the role blood platelets play in the inflammatory process of the mucous membrane of the colon. A high concentration of sP-selectin, which is a marker of blood platelet activation, demonstrates their part in the inflammatory process. The increase in the concentration of sP-selectin correlated positively with the increase in concentration of IL-6. This is why it may be a useful marker of the activity of colitis ulcerosa.