Anders Lasson

The intra-individual variability of faecal calprotectin: a prospective study in patients with active ulcerative colitis.

BACKGROUND AND AIMS Leukocyte-derived proteins in faeces, especially calprotectin, are increasingly used to assess disease activity in ulcerative colitis. The objectives of the present study were to assess the importance of factors related to the stool sampling procedure. METHODS For 2 days, patients with active ulcerative colitis collected two stool samples at each bowel movement. The time of defecation, consistency and presence of blood were self-recorded in a diary. The variability in the concentrations of calprotectin during the day and between two consecutive days was assessed, as was the stability of calprotectin concentrations in samples stored at room temperature. RESULTS Altogether, 18 patients collected 287 stool samples. The intraclass correlation coefficient in pairs of samples from 132 bowel movements was 0.79 (95% CI 0.48-0.90). The median individual coefficient of variation in samples collected during the same day was 52% (4-178). There was a correlation between the level of calprotectin and the time between bowel movements (r = 0.5; p = 0.013). After 3 days at room temperature the calprotectin concentrations in stool samples were unchanged, but after 7 days a significant (p < 0.01) decrease was found (mean 28%; 95% CI 0.10-0.47). CONCLUSION The present data reveal a great variability in the concentrations of calprotectin in stool samples collected during a single day. Since the levels of calprotectin increased with longer time between the bowel movements, it seems most appropriate to analyse stool from the first bowel movement in the morning. Moreover, storage of stool samples at room temperature for more than 3 days is not advisable.

Diagnostic yield of colonoscopy based on symptoms.

Objective. There are only a few data on the diagnostic yield of colonoscopy in different symptoms. The aim of this study was to assess the outcome of colonoscopy in patients with various gastrointestinal symptoms and to estimate the relation between the findings and the presenting symptoms. Material and methods. 1121 consecutive colonoscopies were registered during 1 year. Asymptomatic subjects and patients with known inflammatory bowel disease (IBD) were excluded, leaving 767 eligible for the study. Symptoms, findings and clinical judgement about their relation were recorded. Results. In patients with bleeding symptoms (n=405), serious colonic pathology – cancers and adenomas >1 cm, IBD and angiodysplasia – was found in 54 (13.3%), 83 (20.5%) and 20 (4.9%) patients, respectively; 162 (40%) patients had findings that could be related to the symptom. In 173 subjects with non-bloody diarrhoea, the diagnostic yield was 31.2%, i.e. mostly IBD and microscopic colitis. In 189 subjects with other gastrointestinal symptoms, the diagnostic yield was 13.2%. Serious colonic pathology was found in 8 of 362 (2.2%) subjects examined because of non-bleeding symptoms. Conclusion. The diagnostic yield of colonoscopy is high in patients with bleeding symptoms or diarrhoea, while the prevalence of significant findings is equal to a screening population in patients with other symptoms.

Fecal calprotectin one year after ileocaecal resection for Crohn's disease — A comparison with findings at ileocolonoscopy

BACKGROUND AND AIMS Ileocaecal resection for Crohns disease is commonly performed. The severity of endoscopic lesions in the anastomotic area one year postoperatively is considered to reflect the subsequent clinical course. Fecal calprotectin (FC) has been shown to correlate with the findings at ileocolonoscopy in Crohns disease. The objectives of this study were to assess whether the concentration of FC reflects the endoscopic findings one year after ileocaecal resection and to evaluate the variation of FC in individual patients during 6months prior to the ileocolonoscopy. METHODS Thirty patients with Crohns disease and ileocaecal resection performed within one year were included. Stool samples were delivered monthly until an ileocolonoscopy was performed one year postoperatively. RESULTS One year after surgery the median values of FC were not significantly different between the patients in endoscopic remission (n=17) and the patients with an endoscopic recurrence (189 (75-364) vs 227 (120-1066)μg/g; p=0.25). However, most patients with low values were in remission and all patients with high (>600μg/g) calprotectin values had recurrent disease. The variability of the FC concentration was most pronounced in patients with diarrhea. CONCLUSIONS We found no statistical difference in the concentrations of calprotectin between patients in endoscopic remission and patients with a recurrent disease one year after ileocaecal resection for Crohns disease. However, among the minority of patients with low or high values, FC indicated remission and recurrence, respectively. There was significant variation of the fecal calprotectin concentrations over time, which affects the utility of calprotectin in clinical practice.

Fecal calprotectin levels predict the clinical course in patients with new onset of ulcerative colitis.

Background:The clinical course of ulcerative colitis (UC) is unpredictable. During recent years, the ability of fecal biomarkers to predict relapse in inflammatory bowel disease has been evaluated. The objective of this study was to assess fecal calprotectin (FC) as a predictor of disease recurrence in patients with new onset of UC. Methods:Sixty-nine patients were included. After the initial treatment, patients were followed up after 3 months and then yearly for 3 years. The prognostic role of FC 3 months after the initial therapy was evaluated. Results:The FC levels 3 months after the diagnosis were higher in patients experiencing a relapsing disease course compared with those with a mild disease course during 1 year (median, 263; interquartile range [IQR], 100–634 &mgr;g/g versus median, 102; IQR, 38–225 &mgr;g/g; P = 0.009) and 3 years of follow-up (median, 280; IQR, 102–622 &mgr;g/g versus median, 118; IQR, 39–219 &mgr;g/g; P = 0.01). The area under the receiver operating characteristic curves using calprotectin to predict a relapsing disease course during 1 year and 3 years were 0.69 (95% confidence interval, 0.56–0.82) and 0.70 (95% confidence interval, 0.57–0.83), respectively. In the Kaplan–Meier survival analysis, a FC level >262 &mgr;g/g was associated with an increased risk of a relapsing disease course during the study period (P = 0.003). In logistic regression analysis, only FC and age were found to be independent predictors of having a relapsing disease course. Conclusions:Levels of FC 3 months after the initial therapy in patients with new onset of UC predict the disease course over the following years, and they are of value in the clinical management of these patients.

Concept for a rapid point-of-care calprotectin diagnostic test for diagnosis and disease activity monitoring in patients with inflammatory bowel disease: Expert clinical opinion

No abstract available Keywords: Crohns disease; Diagnostic tests; Inflammatory bowel disease; Irritable bowel syndrome; Ulcerative colitis.

Pharmacological intervention based on fecal calprotectin levels in patients with ulcerative colitis at high risk of a relapse: A prospective, randomized, controlled study

Background Targeted therapy, using biomarkers to assess disease activity in ulcerative colitis (UC), has been proposed. Objective The objective of this study was to evaluate whether pharmacological intervention guided by fecal calprotectin (FC) prolongs remission in patients with UC. Methods A total of 91 adults with UC in remission were randomized to an intervention group or a control group. Analysis of FC was performed monthly, during 18 months. A FC value of 300 µg/g was set as the cut-off for intervention, which was a dose escalation of the oral 5-aminosalicylate (5-ASA) agent. The primary study end-point was the number of patients to have relapsed by month 18. Results There were relapses in 18 (35.3%) and 20 (50.0%) patients in the intervention and the control groups, respectively (p = 0.23); and 28 (54.9%) patients in the intervention group and 28 (70.0%) patients in the control group had a FC > 300 µg/g, of which 8 (28.6%) and 16 (57.1%) relapsed, respectively (p < 0.05). Conclusion Active intervention significantly reduced relapse rates, although no significant difference was reached between the groups overall. Thus, FC-levels might be used to identify patients with UC at risk for a flare, and a dose escalation of their 5-ASA agent is a therapeutic option for these patients.

Diagnostic Performance of Computed Tomography Colonography in Symptomatic Patients and in Patients with Increased Risk for Colorectal Disease

Purpose: To evaluate the diagnostic performance (colorectal lesions) of computed tomography (CT) colonography in 111 patients, a majority of whom were at high risk for colorectal neoplasia. Material and Methods: After bowel preparation, CT colonography was performed, immediately followed by conventional colonoscopy. The diagnostic performance of CT colonography was analyzed relative to lesion size, histological diagnosis, and diagnostic certainty. Results: The sensitivity of CT colonography increased with lesion size (P<0.001), and was 91% (21/23) for lesions ⩾10 mm. All 10 carcinomas and 86% (19/22) of adenomas ⩾5 mm were detected. Unconfirmed or false-positive CT findings were generally small and/or reported with low diagnostic certainty. The specificity of CT colonography would be 45% (30/66; 95% CI 34% to 57%) if patients with findings of any size and any diagnostic certainty were selected for follow-up, and 92% (85/92; 95% CI 85% to 96%) if only patients with CT findings ⩾10 mm classified as certain were selected. Conclusion: CT colonography had a high sensitivity for lesions ⩾5 mm. The diagnostic performance increased with lesion size and degree of diagnostic certainty, and was higher for adenomas.

Anti-TNF Therapy Response in Patients with Ulcerative Colitis Is Associated with Colonic Antimicrobial Peptide Expression and Microbiota Composition

BACKGROUND AND AIMS Anti-tumour necrosis factor [TNF] therapy is used in patients with ulcerative colitis [UC], but not all patients respond to treatment. Antimicrobial peptides [AMPs] and the gut microbiota are essential for gut homeostasis and may be important for treatment outcome. The aim of this study was to determine AMP and microbiota profiles in patients with UC before anti-TNF therapy start and correlate these data to treatment outcome. METHODS Serum and biopsies were obtained from UC patients naïve to biological therapy [n = 56] before anti-TNF therapy start [baseline]. Fecal samples were taken at baseline and Weeks 2 and 6. Quantitative proteomic analysis was performed in mucosal biopsies. Expression of AMPs and cytokines was determined in biopsies and serum. Microbiota analysis of fecal samples was performed using GA-map™ Dysbiosis Test and real-time quantitative polymerase chain reaction [rtPCR]. Treatment response was evaluated 12-14 weeks after baseline. RESULTS At baseline, proteomic analysis of biopsies showed that treatment responders and non-responders had differential expression of AMPs. Eleven AMP and AMP-related genes were analysed by rtPCR in mucosal biopsies and could together discriminate responders from non-responders at baseline. The most important nominators for response were increased expression of defensin 5 and eosinophilic cationic protein. Microbiota analysis revealed lower dysbiosis indexes and higher abundance of Faecalibacterium prausnitzii in responders compared with non-responders at baseline. Also, abundance of F. prausnitzii increased during induction therapy in responders. CONCLUSIONS Anti-TNF therapy responders and non-responders display distinctly separate patterns of mucosal AMP expression and gut microbiota before treatment start. This indicates that intestinal antimicrobial/microbial composition can influence treatment outcome.

Response to infliximab therapy in ulcerative colitis is associated with decreased monocyte activation, reduced CCL2 expression and downregulation of Tenascin C.

BACKGROUND AND AIMS The cellular mechanisms leading to infliximab therapy response in patients with ulcerative colitis (UC) are incompletely known. We therefore investigated early effects of infliximab therapy on monocytes and associated chemokines linked to clinical therapy response in UC patients. METHODS Blood and biopsies were obtained from anti-TNF therapy-naïve UC patients (n = 43) before (baseline) and during induction therapy with infliximab. Therapy response was evaluated at Week 14. Expression of monocyte activation markers and levels of chemokines in serum and biopsies were determined. Quantitative proteomic analysis was performed in cultured mucosal biopsies, and obtained data was validated in serum. RESULTS In therapy responders, but not in non-responders, infliximab reduced blood monocyte expression of CD14 and CD86, 2 weeks after therapy commenced, relative to baseline. Serum CCL2 levels were decreased only among therapy responders at Week 2 and Week 14, relative to baseline. These data corresponded with lower levels of CD14, CD86 and CCL2 in intestinal tissue in responders as compared with non-responders at Week 14. Proteomic analysis of cultured biopsies showed that infliximab induced a reduction in Tenascin C that predicted downregulation of CCL2. Therapy responders, but not non-responders, had decreased serum Tenascin C levels at Week 2 and Week 14, relative to baseline. CONCLUSIONS Infliximab therapy response in UC patients is associated with reduced monocyte activation and serum levels of CCL2 2 weeks after therapy commencement. In therapy responders, infliximab influenced Tenascin C, which might be a regulator of CCL2 expression and important for induction of the clinical therapy response.

Global mucosal and serum cytokine profile in patients with ulcerative colitis undergoing anti-TNF therapy.

Abstract Background and objective. The knowledge of the effects of anti-tumour necrosis factor (TNF) treatment on the global cytokine profile in patients with ulcerative colitis (UC) is limited. A better understanding of these mechanisms could improve the ability to select patients that should undergo the therapy. Therefore, the aim was to determine the global mucosal and serum cytokine profile before and during induction therapy with anti-TNF in UC patients. Materials and methods. In total, mucosal biopsies (n = 28) and serum samples (n = 42) were collected from UC patients (total n = 48) before anti-TNF therapy. At week 14 response to the therapy was evaluated and again mucosal biopsies (n = 14) and serum samples (n = 42) were collected. Quantitative real-time PCR was used to determine mucosal cytokine mRNA expression and the MSD MULTI-ARRAY assay system platform was used for analysis of cytokines in serum. The global cytokine profile was evaluated by multivariate factor analysis. Results. At baseline, the global profile of mucosal cytokine mRNA expression and serum cytokines discriminated therapy responders from non-responders. Responders had lower mucosal mRNA expression of interleukin 1β (IL-1β), IL-17A, IL-6 and interferon γ (IFN-γ) than non-responders. Fourteen weeks after therapy start mucosal IL-1β and IL-6 were down-regulated in therapy responders but not in non-responders. At week 14, serum levels of IL-6 were decreased in therapy responders whereas IFN-γ and IL-12p70 were increased in non-responders. Conclusions. Our data suggest that patients with a therapy failure have a more severe pro-inflammatory cytokine profile before start of anti-TNF treatment, which is less well suppressed by the treatment as compared to therapy responders.