Faecal calprotectin in children with clinically quiescent inflammatory bowel disease

Abstract

Objective. The use of faecal calprotectin as a surrogate marker for intestinal inflammation is emerging. However, the data on faecal calprotectin during maintenance therapy in children with inflammatory bowel disease, IBD, are sparse. Our aim was to study faecal calprotectin levels in paediatric IBD during clinically quiescent disease and to investigate if high levels were associated with a flare-up of the disease. Subjects and methods. Faecal calprotectin level was measured in 72 children with paediatric IBD in clinical remission (median age 13 years). Of these, 37 children had been in clinical remission for more than a year, 20 for 6–12 months and 15 for 3 to <6 months. The clinical outcome of the patients was followed up to the first relapse or up to 12 months. Results. When in clinical remission, 35% (25/72) of the children had normal faecal calprotectin (<100 μg/g) and 13% (9/72) a very high level (>1000 μg/g) while not reporting symptoms. A clinical relapse occurred in 35% (25/72) during the subsequent 12 months. When in clinical remission, the predictive value of faecal calprotectin for an overt relapse was low ranging from 0.396 to 0.429 for faecal calprotectin values >100 μg/g or >1000 μg/g, respectively. The negative predictive value was 0.75 for values <100 μg/g. Conclusions. In paediatric IBD, subjective symptoms and clinical assessment associate poorly with the levels of faecal calprotectin. During maintenance medication in colonic disease, the probability of staying in clinical remission for a subsequent year is high if faecal calprotectin value is low.     

Change of diagnosis during the first five years after onset of inflammatory bowel disease: Results of a prospective follow-up study (the IBSEN Study)

Objective. An exact diagnosis of inflammatory bowel disease (IBD) and further subclassification may be difficult even after clinical, radiological and histological examinations. A correct subclassification is important for the success of both medical and surgical therapeutic strategies, but there is a dearth of information available on the frequency of changes in diagnosis in population-based studies. The objective of this work was prospectively to re-evaluate the diagnosis in an unselected cohort of IBD patients during the first five years after the initial diagnosis. Material and methods. Patients classified as IBD or possible IBD in the period 1990–94 (the IBSEN cohort) had their diagnosis re-evaluated after 1 and 5 years. Initially, the patients were classified as ulcerative colitis (UC), Crohn's disease (CD), indeterminate colitis (IC) or possible IBD. At the 5-year visit, patients were classified as UC, CD or non-IBD. Results. A total of 843 patients (518 UC, 221 CD, 40 IC and 64 possible IBD) were identified. Clinical information was available for 94% of the patients who survived after 5 years. A change in diagnosis was found in 9% of the patients initially classified as UC or CD. A change to non-IBD was more frequent than a change between UC and CD. A large proportion of patients initially classified as IC or possible IBD were diagnosed as non-IBD after 5 years (22.5% versus 50%). When IBD was confirmed in these groups, UC was more frequent than CD. Two changes in diagnosis during follow-up were observed in 2.8% of the patients; this was more frequent in patients initially classified as IC or possible IBD. Conclusions. There are obvious diagnostic problems in a minority of patients with IBD; a systematic follow-up is therefore important in these patients.     

Clinical implications of assay specific differences in f-calprotectin when monitoring inflammatory bowel disease activity over time

Objective: With several faecal calprotectin (FC) assays on the market, it has been difficult to define a uniform threshold for discriminating between remission and active disease in patients with inflammatory bowel disease (IBD). We aimed to compare the results of different FC-assays in IBD patients, followed over time.

Material and methods: IBD patients provided faecal samples and reported clinical activity every third month prospectively over a two year period. FC was measured with two ELISA – (Bühlmann and Immunodiagnostik) and one automated fluoroimmunoassay (Phadia).

Results: In total, 13 patients provided 91 faecal samples. The median (IQR) concentration of FC was higher at active disease than at remission for all assays: Bühlmann 845 (1061–226) μg/g versus 62 (224–39) μg/g, Phadia 369 (975–122) μg/g versus 11 (52–11) μg/g, and Immundiagnostik 135 (302–69) μg/g versus 8 (56–4) μg/g. The Bühlmann assay produced the largest absolute difference but the corresponding relative difference seemed to be more pronounced when analysed by the Phadia – (ratio of means 8.5; 95% CI 3.3–21.9) or the Immundiagnostik assay (ratio of means 7.4; 95% CI 3.1–17.6) than by the Bühlmann assay (ratio of means 5.3; 95% CI 2.7–10.6). Consequently, the specificity for discriminating active disease from remission varied between assays (34–75%) when the cut-off 50?μg/g was used, whereas the differences in sensitivity were less pronounced.

Conclusions: Cross-comparisons revealed overall poor agreement between the assays as well as differences in the dynamics of FC. These findings suggest that standardisation of the method is needed to implement FC as a disease monitoring tool at large-scale.     

The risk of inflammatory bowel disease flares after fecal microbiota transplantation: Systematic review and meta-analysis

Several studies have suggested worsening in inflammatory bowel disease (IBD) activity following fecal microbiota transplantation (FMT). We aimed to assess the risk of worsening in IBD activity following FMT. An electronic search was conducted using MEDLINE (1946-June 2016), EMBASE (1954-June 2016) and Cochrane Central Register of Controlled Trials (2016). Studies in which FMT was provided to IBD patients for IBD management or (Clostridium difficile infection) CDI treatment were included. The primary outcome was the rate of worsening in IBD activity. Results: Twenty-nine studies with 514 FMT-treated IBD patients were included. Range of follow up was 4 weeks to 3 y. The pooled rate of IBD worsening was 14.9% (95% CI 10–21%). Heterogeneity was detected: I2 D 52.1%, Cochran Q test D 58.1, p D 0.01. A priori subgroup analyses were performed. Although not significant, the pooled rate of worsening in IBD activity following FMT for CDI (22.7% (95% CI: 13–36%)) was higher compared with FMT for IBD (11.1% (95% CI 7–17%)). Rates of worsening in IBD after lower GI FMT delivery revealed a higher rate of worsening in IBD activity (16.5% (95% CI: 11–24%)) compared with upper GI delivery (5.6% (95% CI: 2–16%)). Rates of worsening in high quality studies and randomized controls trials (RCTS) suggested a marginal risk of worsening in IBD activity (4.6%, (95% CI: 1.8–11%). Rates of IBD worsening are overall marginal across high quality RCTS. It is unknown if the FMT itself led to the worsening of IBD in this small fraction or if this represents alternative etiologies.     

Management of inflammatory bowel disease in adults

Optimal care of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis, requires a broad understanding of disease pathophysiology and therapeutic alternatives. The goals of therapy are accurate diagnosis and timely treatment to both induce and maintain a clinical remission and improve patient quality of life. Most patients can be adequately treated using a combination or aminosalicylates, antibiotics, and corticosteroids, though many patients with Crohn's disease will require immunomodulators, such as azathioprine or 6-mercaptopurine. The development of novel biologic therapies, particularly infliximab, have dramatically improved our ability to medically manage more severe Crohn's disease and ulcerative colitis patients. This review will focus on the medical management of inflammatory bowel disease in adults.     

Progression of inflammatory bowel disease in China

The epidemiology and phenotype of inflammatory bowel disease (IBD) in the Chinese population is not well-known. We performed a comprehensive search of the Chinese biomedical literature database from 1989 to 2007 using the following key words: inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD). The investigation of hospitalized IBD patients from 1990 to 2003 was also carried out in 23 medical centers of 11 cities over China. There are some notable epidemiological and phenotypical differences between Chinese IBD and Caucasian IBD, including a lack of familial clustering, male predominance, a relatively later onset of the illness with no second peak age occurrence after 50 years old, a milder clinical course, less extra-intestinal manifestations and complications, and less fistulous and peri-anal complications in Chinese CD. The data indicate an increased incidence of IBD in China with many complicated clinical problems, which offers potential opportunities to study the disease prospectively and identify the etiological factors, leading also to the better management of this disease in China.     

Finnish patients with inflammatory bowel disease have fewer symptoms and are more satisfied with their treatment than patients in the previous European survey

Objective. Symptoms associated with inflammatory bowel diseases (IBD) have a negative impact on quality of life. The purpose of this study was to assess the quality of life in a large group of Finnish IBD patients and to compare it with that observed in a recent survey covering several other European countries. Material and methods. The European Federation of Crohn's and Ulcerative Colitis Associations (EFCCA) questionnaire, comprising questions about IBD symptoms, diagnosis, therapy, extraintestinal manifestations and their impact on patients’ quality of life, was sent to 3852 members of the Finnish Crohn and Colitis Association. The response rate was 63%. Results. IBD was diagnosed by a specialist in over 96% of cases and 94% of patients were continuously followed-up by a specialist. Fifty-eight percent of the patients had had IBD symptoms for over a year before consulting a specialist. The frequency of symptoms was lower in the Finnish patients and 93% of patients were satisfied with their current treatment compared with 76% in the European survey. For Crohn's disease, the rate of surgery was lower than that in the European survey (43% versus 52%). The patients reported improved quality of life after surgery, but 67% of patients with Crohn's disease and 34% with ulcerative colitis reported recurrence of symptoms. Comorbidity with ankylosing spondylitis was 22 times more common than in the general Finnish population and 49% of the patients suffered from joint pain. Conclusions. Finnish IBD patients are more satisfied with their treatment than those studied in the European survey. In Finland, gastroenterologists are usually responsible for the care, but the delay before the diagnosis remains long.     

Body mass index and risk of inflammatory bowel disease: A systematic review and dose‐response meta‐analysis of cohort studies of over a million participants

The relationship between body mass index (BMI) and risk of inflammatory bowel disease (IBD) is controversial. We performed a dose‐response meta‐analysis to investigate the association between BMI and risk of incident ulcerative colitis (UC) and Crohn's disease (CD) using prospective cohort studies. A systematic search was conducted in MEDLINE/PubMed, SCOPUS, Cochrane, and Web of Science databases from inception to January 2019. DerSimonian and Laird random‐effects model was used to estimate combined hazard ratios (HRs). Overall, 882 articles were screened, and 42 full‐text articles were reviewed for inclusion using the study eligibility criteria. Five studies evaluated the association between BMI and IBD with 1 044 517 participants. Pooled results showed a significant association between participants affected by obesity and risk of CD (HR: 1.42, 95% CI: 1.18‐1.71, I²: 0.00). There was a significant nonlinear association between BMI and risk of CD (P = .01, coeff = 0.5024). Pooled results did not show any significant association between being underweight and risk of UC (HR: 1.07, 95% CI: 0.96‐1.19, I²: 0.00) or CD (HR: 1.11, 95% CI: 0.93‐1.31, I²: 12.8). There was no difference in the risk for UC among participants affected by obesity compared with participants categorized as having normal BMI (HR: 0.96, 95% CI: 0.80‐1.14, I²: 8.0). This systematic review and meta‐analysis identified significant dose‐response relationship between being affected by obesity, as a risk factor, and incidence of CD.     

Inflammatory bowel disease: Established and evolving considerations on its etiopathogenesis and therapy

Modern studies of inflammatory bowel disease (IBD) pathogenesis have been pursued for about four decades, a period of time where the pace of progress has been steadily increasing. This progress has occurred in parallel with and is largely due to developments in multiple basic scientific disciplines that range from population and social studies, genetics, microbiology, immunology, biochemistry, cellular and molecular biology, and DNA engineering. From this cumulative and constantly expanding knowledge base the fundamental pillars of IBD pathogenesis appear to have been identified and consolidated during the last couple of decades. Presently there is a general consensus among basic IBD investigators that both Crohn's disease (CD) and ulcerative colitis (UC) are the result of the combined effects of four basic components: global changes in the environment, the input of multiple genetic variations, alterations in the intestinal microbiota, and aberrations of innate and adaptive immune responses. There is also agreement on the conclusion that none of these four components can by itself trigger or maintain intestinal inflammation. A combination of various factors, and most likely of all four factors, is probably needed to bring about CD or UC in individual patients, but each patient or set of patients seems to have a different combination of alterations leading to the disease. This would imply that different causes and diverse mechanisms underlie IBD, and this could also explain why every patient displays his or her own clinical manifestations and a personalized response to therapy, and requires tailored approaches with different medications. While we are becoming increasingly aware of the importance of this individual variability, we have only a superficial notion of the reasons why this occurs, as hinted by the uniqueness of the genetic background and of the gut flora in each person. So, we are apparently facing the paradox of having to deal with the tremendous complexity of the mechanisms responsible for chronic intestinal inflammation in the setting of each patient's individuality in the response to this biological complexity. This obviously poses considerable challenges to reaching a full understanding of IBD pathogenesis, but being aware of the difficulties is the first step in finding answers to them.     

Incidence and clinical presentation of IBD in children: Comparison between prospective and retrospective data in a selected Norwegian population

Objective. The results of recent research suggest that there is an increasing incidence of inflammatory bowel disease (IBD) among children. Newly diagnosed IBD was compared between two consecutive 6-year periods in the same catchment area of southeastern Norway. Material and methods. Children subjected to endoscopy from 1993 to 2004 were recorded retrospectively in the first 6-year period and prospectively for the subsequent period. The mean size of the child population under 16 years in the area was 70,500. The study reports on incidence numbers, age at diagnosis, disease distribution and clinical presentation at diagnosis. Results. There were 23 incident cases of IBD in the first period and 25 in the subsequent period. The rates of Crohn's disease (CD) for the two periods were, respectively, 1.95 and 3.64, and for ulcerative colitis (UC) 3.67 and 2.05/100,000 children/year. Total incidence rates of IBD for the two periods were 5.6 and 5.7, respectively, similar to the findings of the IBSEN study of 1990–94. The change in CD and UC rates from the first to the second period can be explained by better methods of diagnosis. Conclusions. The total incidence of IBD was not changed between time periods, whereas a trend towards an increase in CD and a reduction in UC was recorded. The incidence rates are in accordance with previously reported national and international data from the past decade. The extent of disease in CD and UC may indicate a serious prognosis of IBD among children.     

Recent developments in the treatment of inflammatory bowel disease

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases that have been treated with corticosteroids, 5‐aminosalicates and thiopurines, but therapeutic options have been broadened with the arrival of anti‐tumor necrosis factor antibodies. In this article we reviewed the current evidence‐based approach to inflammatory bowel disease, the modifications that have been made to existing therapies and discussed new drugs that have shown success in clinical trials. The new drugs discussed here are those that disturb lymphocyte homing to the gut (natalizumab, vedolizumab and anti‐mucosal addressin cellular adhesion molecule); one that blocks interleukin (IL)‐12 as well as the IL‐23/T helper 17 (Th17) axis (ustekinumab) and one that blocks the signaling of multiple cytokines (tofacitinib).     

Microbiome and metabolome in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease of unknown etiology, involving complex interactions between the gut microbiome and host immune response. The microbial dysbiosis is well documented in IBD and significantly influences the host metabolic pathways. Thus, a metabolomic fingerprint resulting from the influence of gut dysbiosis in IBD could aid in assessing the disease activity. PubMed, Medline, Science Direct, and Web of Science were searched for studies exploring the association between microbiome and metabolome in IBD patients in the last 5 years. Additionally, references of cited original articles and reviews were further assessed for relevant work. We provide a literature overview of the recent metabolomic studies performed on patients with IBD. The findings report alterations in the metabolite levels of these patients. We also discuss the gut dysbiosis observed in IBD and its influence on host metabolic pathways such as lipids, amino acids, short-chain fatty acids, and others. IBD, being a chronic idiopathic disease, requires routine monitoring. The available non-invasive markers have their limitations. The metabolite changes account for both dysbiosis and its influence on the host's immune response and metabolism. A metabolome approach would thus facilitate the identification of surrogate metabolite markers reflecting the disease activity.     

Visualising E-selectin in the detection and evaluation of inflammatory bowel disease

Background—Vascular endothelial E-selectin expression is induced by proinflammatory cytokines andcontributes to accumulation of leucocytes in tissues.
Aims—To investigate the role ofE-selectin in inflammatory bowel disease (IBD).
Methods—E-selectin expression wasassessed in patients with ulcerative colitis and Crohn's disease bymeasuring the concentration of circulating soluble E-selectin(sE-selectin) using ELISA, by immunohistochemistry of colonic biopsyspecimens, and by abdominal immunoscintigraphy after injectingradiolabelled F(ab')₂ fragment of a monoclonalanti-E-selectin antibody. The value of scintigraphy usinganti-E-selectin was judged by a prospective comparative study ofautologous leucocyte scanning and E-selectin antibody scanning in 17 patients with IBD.
Results—Circulating sE-selectin waselevated in patients with clinically active disease. Tissue expressionof E-selectin was enhanced in patients with active inflammation, withweak or absent expression in inactive disease and healthy controls.In-111 labelled anti-E-selectin scintiscans were compared with Tc-99mlabelled leucocyte scans performed 24 hours earlier. Twelve patientshad areas of active inflammation on leucocyte scan while 11 patients had positive E-selectin scans. The results of the two scans were concordant in 14 patients, with those positive for both (10/17) showingsimilar disease localisation and extent.
Conclusions—Tissue E-selectinand circulating sE-selectin are increased during active inflammatorybowel disease. Anti-E-selectin imaging with radiolabelled monoclonalantibody identified areas of inflammation in Crohn's disease andulcerative colitis. The technique should prove useful clinically foridentifying the site and extent of disease.

Keywords:E-selectin; inflammatory bowel disease; Crohn'sdisease; ulcerative colitis

     

Soluble urokinase plasminogen activator receptor suPAR as a marker for inflammation in pediatric inflammatory bowel disease

Abstract

Objective. In inflammatory bowel disease (IBD), more means to monitor early therapeutic response are needed. In pediatric IBD, blood inflammatory markers erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) may be low in 10 to 20% of patients with severe disease. Recently, soluble urokinase plasminogen activator receptor (suPAR) was described as a potential blood inflammatory marker in adult IBD. Methods. We tested the performance of suPAR by the start of therapy with glucocorticoids (n = 19) or TNF-α-antagonist (n = 16) in pediatric IBD (Crohn's disease n = 19, ulcerative colitis (UC) n = 16). Results. The levels of suPAR were low in both patient groups studied. There was no difference in the values regarding the presence of Crohn's disease or ulcerative colitis. Thus, all analyses were performed on the entire sample set. Glucocorticoid therapy, however, resulted in a significant decline in suPAR levels from a median of 3.06 to 2.54 ng/ml (p < 0.01). In contrast, TNF-α-antagonist had no effect. The suPAR levels did not associate with ESR or CRP or fecal calprotectin (FC). Conclusions. In pediatric IBD, the suPAR levels in blood are low and do not reflect the level of intestinal inflammation assessed with FC. The introduction of corticoids, however, results in a decline of suPAR levels in blood but not reflect therapeutic response to TNF-α-antagonist. Thus, suPAR is of limited value in assessing systemic inflammatory responses in pediatric IBD.     

Monozygotic twins with Crohn's disease and ulcerative colitis: a unique case report

Background—A large number of monozygotic anddizygotic twin pairs with inflammatory bowel disease have beenreported. To date no twin pair has developed phenotypically discordantinflammatory bowel disease. This case report is the first documentedoccurrence of discordant inflammatory bowel disease occurring inmonozygotic twins.
Case report—Twenty two year old identical maletwins presented within three months of each other with inflammatorybowel disease that proved to be discordant in overall disease type,disease distribution, clinical course, and histopathological findings. Twin 1 developed a severe pancolitis necessitating total colectomy while twin 2 developed a predominantly distal patchy colitis with frequent granulomas, controlled by aminosalicylates. Twin 1 was antineutrophil cytoplasmic antibody (ANCA) negative at the time oftesting while twin 2 (Crohn's disease) was ANCA positive.Significantly, the twins possessed the HLA type DR3-DR52-DQ2 previouslyassociated with extensive colitis.
Conclusion—This case report confirms the importantrole played by genetic factors in the development of inflammatory bowel disease. It also highlights the crucial role of undeterminedenvironmental agents in dictating disease expression and phenotype.

Keywords:monozygotic twins; ulcerative colitis; Crohn'sdisease; inflammatory bowel disease

     

Granulocyte,monocyte/macrophage apheresis for inflammatory bowel disease: The first 100 patients treated in Scandinavia

Objective. Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with active ulcerative colitis and Crohn's disease. Preliminary data have indicated that this type of therapy is safe and efficacious, and large sham-controlled studies are currently in progress. In Scandinavia, a substantial number of patients with chronic inflammatory bowel disease have already received leukocyte apheresis on a compassionate use basis and the aim of this study was to report the clinical outcome and adverse events in the first patients treated. Material and methods. Clinical details of the first consecutive 100 patients with inflammatory bowel disease treated with granulocyte, monocyte/macrophage (Adacolumn) apheresis in Scandinavia were prospectively registered. Median length of follow-up was 17 months, (range 5–30). Results. The study population comprised 52 patients with ulcerative colitis, 44 patients with Crohn's disease and 4 patients with indeterminate colitis. In 97 patients the indication for Adacolumn treatment was steroid-refractory or steroid-dependent disease. Clinical remission was attained in 48% of the patients with ulcerative colitis, and an additional 27% had a clinical response to the apheresis treatment. The corresponding figures for patients with Crohn's disease were 41% and 23%, respectively. Complete steroid withdrawal was achieved in 27 out of the 50 patients taking corticosteroids at baseline. Adverse events were reported in 15 patients and headache was most frequently reported (n=7). Conclusions. Granulocyte, monocyte/macrophage apheresis treatment seems to be a valuable adjuvant therapy in selected patients with refractory inflammatory bowel disease. The risk for toxicity or severe adverse events appears to be low.     

Direct health‐care cost utilization in Hong Kong inflammatory bowel disease patients in the initial 2 years following diagnosis

Background and Aim

There are scanty data on the health‐care utilization from Asia where the incidence of inflammatory bowel disease (IBD) is rising rapidly. We aim to determine the direct health‐care costs in the first 2 years of diagnosis in an IBD cohort from Hong Kong and the factors associated with high cost outliers.

Methods

This is a retrospective cohort study that included patients newly diagnosed with IBD in a territory‐wide IBD registry. Patients' clinical information, hospitalization records, investigations, and IBD treatments were retrieved for up to 2 years following diagnosis of IBD.

Results

Four hundred and thirty‐five newly diagnosed IBD patients were included: 198 with Crohn's disease and 237 with ulcerative colitis. Total direct medical expenditure for this cohort 2 years after the IBD diagnosis was $7 072 710: hospitalizations (33%), 5‐aminosalicylic acid (23%), imaging and endoscopy (17%), outpatient visits (10%), surgery (8%), and biologics (6%). Mean direct medical costs per patient‐year were significantly higher for Crohn's disease ($9918) than ulcerative colitis ($6634; P, 0.001). The total direct health‐care cost decreased significantly after transition to the second year (P < 0.01). High cost (> 90th percentile) outliers were associated with surgery (OR 7.1, 95% CI 2.9–17.2) and low hemoglobin on presentation (OR 0.83, 95% CI 0.70–0.96).

Conclusions

Hospitalization and 5‐aminosalicylic acid usage accounted for 56% of total direct medical costs in the first 2 years of our newly diagnosed IBD patients. Direct health‐care costs were higher in the first year compared with the second year of diagnosis. Surgery and low hemoglobin on presentation were associated with high cost outliers.