Roberta Caccaro

Measuring disease activity in Crohn's disease: what is currently available to the clinician

Crohn’s disease (CD) is a chronic inflammatory bowel disease characterized by a relapsing-remitting clinical behavior and dominated by intestinal inflammation. Being a chronic disorder that with time develops into a disabling disease, it is important to monitor the severity of inflammation to assess the efficacy of medication, rule out complications, and prevent progression. This is particularly true now that the goals of treatment are mucosal healing and deep remission. Endoscopy has always been the gold standard for assessing mucosal activity in CD, but its use is limited by its invasiveness and its inability to examine the small intestine, proximal to the terminal ileum. Enteroscopy and the less invasive small bowel capsule endoscopy enable the small bowel to be thoroughly explored and scores are emerging for classifying small bowel disease activity. Cross-sectional imaging techniques (ultrasound, magnetic resonance, computed tomography) are emerging as valid tools for monitoring CD patients, assessing inflammatory activity in the mucosa and the transmucosal extent of the disease, and for excluding extra-intestinal complications. Neither endoscopy nor imaging are suitable for assessing patients frequently, however. Noninvasive markers such as C-reactive protein, and fecal biomarkers such as calprotectin and lactoferrin, are therefore useful to confirm the inflammatory burden of the disease and to identify patients requiring further investigations.

The GerdQ questionnaire and high resolution manometry support the hypothesis that proton pump inhibitor-responsive oesophageal eosinophilia is a GERD-related phenomenon.

Little is known about the relationship between proton pump inhibitor‐responsive oesophageal eosinophilia (PPI‐REE), eosinophilic esophagitis (EoE) and gastro‐oesophageal reflux disease (GERD).

A case of anorexia nervosa with comorbid Crohn's disease: beneficial effects of anti-TNF-α therapy?

This case report describes a 26-year-old woman affected by long-lasting anorexia nervosa (AN) and Crohns disease. Worsening of the bowel illness led to the prescription of immunosuppressive therapy (biologic infliximab for 4 months, followed by adalimumab for 6 months) and referral to our Eating Disorders Unit. Although she initially demonstrated denial of her eating disorder, in a few months she gradually improved her weight and psychopathology. Crohns disease can worsen AN by modifying hunger and energy expenditure through the effects of TNF-α and IL-6, pro-inflammatory cytokines which moderate leptin and melanocortin signaling. Previous studies have observed the antidepressant effects of TNF antagonist in patients with treatment-resistant depression with high baseline inflammatory biomarkers. Our case report suggests that future studies are needed to clarify the existence, patterns, and extent of increased inflammatory markers in patients with AN, and whether they determine clinical features or identify subgroups of patients. Potential therapeutic significance of above issues remains to be determined.

Clinical utility of calprotectin and lactoferrin in patients with inflammatory bowel disease: is there something new from the literature?

The identification of noninvasive biomarkers is still one of the major issue for gastroenterologists dealing with inflammatory bowel disease patients, due to the chronicity of these conditions and the early onset of symptoms in the majority of cases. Research attention has focused mainly on fecal proteins, especially calprotectin and lactoferrin, and most of the published data are reassuring about their applicability in the diagnosis and monitoring of these patients. However, there are still pending questions regarding the reliability of fecal proteins especially in the era of mucosal healing and biologics.

Noninfectious interstitial lung disease during infliximab therapy: Case report and literature review

Pulmonary abnormalities are not frequently encountered in patients with inflammatory bowel diseases. However, lung toxicity can be induced by conventional medications used to maintain remission, and similar evidence is also emerging for biologics. We present the case of a young woman affected by colonic Crohns disease who was treated with oral mesalamine and became steroid-dependent and refractory to azathioprine and adalimumab. She was referred to our clinic with a severe relapse and was treated with infliximab, an anti-tumor necrosis factor α (TNF-α) antibody, to induce remission. After an initial benefit, with decreases in bowel movements, rectal bleeding and C-reactive protein levels, she experienced shortness of breath after the 5(th) infusion. Noninfectious interstitial lung disease was diagnosed. Both mesalamine and infliximab were discontinued, and steroids were introduced with slow but progressive improvement of symptoms, radiology and functional tests. This represents a rare case of interstitial lung disease associated with infliximab therapy and the effect of drug withdrawal on these lung alterations. Given the increasing use of anti-TNF-α therapies and the increasing reports of pulmonary abnormalities in patients with inflammatory bowel diseases, this case underlines the importance of a careful evaluation of respiratory symptoms in patients undergoing infliximab therapy.

Clinical utility of calprotectin and lactoferrin as markers of inflammation in patients with inflammatory bowel disease

Crohn’s disease and ulcerative colitis have a feature in common (i.e., chronic inflammation). Their clinical management requires repeated assessments; endoscopy with histological examination remains the gold standard for detecting and quantifying intestinal inflammation. An ideal marker should be quick and easy to obtain noninvasively, and should be inexpensive and reproducible. Several laboratory tests have been studied but, to date, a disease marker is not yet available. A combination of signs and symptoms, laboratory findings and imaging techniques is consequently still needed for assessing disease activity and prognosis. In recent years, research has drawn attention to fecal markers owing to their specificity for intestinal inflammation, ease of sample collection, availability of commercial immunoassays and convenience. Biological markers have been used to assess inflammatory bowel disease patients for the purposes of their clinical management, monitoring disease activity, predicting relapses, assessing prognosis and monitoring response to treatment.

Clinical, endoscopic, histological and radiological characteristics of Italian patients with eosinophilic oesophagitis

BACKGROUND Limited data are available on eosinophilic oesophagitis in Italy. AIM To evaluate typical features of eosinophilic oesophagitis patients in a tertiary centre. METHODS 973 consecutive patients with dysphagia and/or bolus impaction were prospectively enrolled and underwent upper endoscopy for eosinophilic oesophagitis (≥15 eosinophils in at least one high-power field [hpf] and no response to acid suppressants). Demographic and multiple clinical factors were collected. RESULTS 45 patients (80% males, mean age 35±16) with incident eosinophilic oesophagitis (mean eosinophil peak count 57.2±40.6/hpf) were enrolled. 32 patients complained of solids dysphagia (71%), and 29 of bolus impaction (64%). Endoscopy found rings in 20 (44%), furrows in 9 (20%), whitish exudates/plaques in 12 (27%), crêpe paper in 7 (13%) and normal findings in 14 patients (31%). Endoscopic and radiologic stenosis occurred in 20 (44%) and 23 (51%), respectively. Ten patients had proton pump inhibitor-oesophageal eosinophilia (22%). Topic fluticasone was effective in 28 of the remaining cases (62%), while 7 required additional treatments (16%). CONCLUSION Eosinophilic oesophagitis prevalence was 12% in patients with dysphagia and/or bolus impaction, emphasizing the importance of this disease in Italy. Despite different environmental factors and dietary habits, Italian patients with eosinophilic oesophagitis present similar characteristics to those of other Western counties.

Improving IBD diagnosis and monitoring by understanding preanalytical, analytical and biological fecal calprotectin variability

Abstract Background: The appropriate clinical use of fecal calprotectin (fCal) might be compromised by incomplete harmonization between assays and within- and between-subjects variability. Our aim was to investigate the analytical and biological variability of fCal in order to provide tools for interpreting fCal in the clinical setting. Methods: Experiments were conducted to investigate the effects of temperature and storage time on fCal. Thirty-nine controls were enrolled to verify biological variability, and a case-control study was conducted on 134 controls and 110 IBD patients to compare the clinical effectiveness of three different fCal assays: ELISA, CLIA and turbidimetry. Results: A 12% decline in fCal levels was observed within 24 h following stool collection irrespective of storage temperature. Samples were unstable following a longer storage time interval at room temperature. Within- and between-subjects fCal biological variability, at 31% and 72% respectively, resulted in a reference change value (RCV) in the region of 100%. fCal sensitivity in distinguishing between controls and IBD patients is satisfactory (68%), and the specificity high (93%) among young (<65 years), but not among older (≥65 years) subjects (ROC area: 0.584; 95% CI: 0.399–0.769). Among the young, assays have different optimal thresholds (120 μg/g for ELISA, 50 μg/g for CLIA and 100 μg/g for turbidimetry). Conclusions: We recommend a standardized preanalytical protocol for fCal, avoiding storage at room temperature for more than 24 h. Different cutoffs are recommended for different fCal assays. In monitoring, the difference between two consecutive measurements appears clinically significant when higher than 100%, the fCal biological variability-derived RCV.

Randomized controlled trials in maintenance of remission in Crohn's disease.

Maintenance of medically induced remission is a clinical challenge in Crohns disease (CD), since it is a chronic disease and that often occurs in young people. The introduction of immunosuppressors and biologics has significantly improved the management of these patients, however efficacy and safety of these treatments in the very long term still needs clarification. Furthermore, scientific research is driven more into new drugs to induce remission rather then maintenance.

P.54 CMV SPECIFIC T-CELL RESPONSE IS CONSERVED IN IBD PATIENTS

Background and aim: Excessive Th1-mediated immune response promotes pathogenic inflammation in the gut. Indeed, therapeutic interventions targeting Th1-type cytokines have already shown great promise for the treatment of patients with inflammatory bowel diseases (IBD). The aryl hydrocarbon receptor (AhR), a cytosolic transcription factor best known for mediating the dioxin-toxicity, has been recently reported to modulate Th cell responses. Aim: To evaluate if AhR-signalling controls pathogenic Th1 cell-mediated inflammation in the gut. Material and methods: 6-formylindolo[3,2-b]carbazole (FICZ), a highaffinity ligand of AhR, or the AhR antagonist, 2-metyl-2H-pyrazole-3carboxylic acid, were intraperitoneally administered to mice with acute 2,4,6trinitrobenzene-sulfonic acid (TNBS) or chronic dextrane-sodium-sulfate (DSS). Lamina propria mononuclear cells (LPMC) were analyzed for inflammatory and anti-inflammatory molecules by real-time-PCR and flow citometry. To evaluate whether the anti-inflammatory effect of AhR was mediated by IL22, mice were injected with a neutralizing IL-22 antibody 6 hours prior to being treated with FICZ. Th1-related cytokines were also analyzed in Crohn’s disease (CD) mucosal explants and LPMC either left untreated or treated with FICZ. Results: FICZ-treated mice were largely protected against TNBS and DSS colitis, and showed a marked down-regulation of pro-inflammatory molecules, such as IFN-gamma, TNF-alpha, IL-6, IL-12, and T-bet. This was associated with induction of IL-22, and no change in the fractions of IL-10 or Foxp3positive cells. Flow-cytometry analysis revealed that both T and non-T cells were major sources of IL-22 in FICZ-treated mice. Notably, neutralization of endogenous IL-22 with the blocking IL-22 antibody largely prevented the FICZ-mediated therapeutic effect in mice with TNBS-colitis. Abrogation of AhR-signaling reduced colonic IL-22 expression, thus leading to the development of a severe TNBS-colitis. Finally, we showed that FICZ markedly reduced Th1-related markers in CD mucosal explants and LPMC. Conclusions: Data show that AhR-driven signals inhibit pathogenic responses in the gut, and suggest that AhR-related compounds may be therapeutically useful in human IBD, such CD. # G. Inflammatory bowel diseases 1. Basic science