Prevalence, Pathogenesis and Management of Anemia in Inflammatory Bowel Disease: An IG-IBD Multicenter, Prospective, and Observational Study.

BACKGROUND: Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD), with a 6% to 74% prevalence and a negative impact on patient survival and quality of life, although the prevalence is apparently declining due to improved disease treatment. We aimed to investigate the prevalence, pathogenesis, and clinical correlates of anemia in Italian patients with IBD. METHODS: A multicenter, prospective, observational study, involving 28 Italian gastroenterology centers, was conducted to investigate the epidemiology and consequences of IBD-associated anemia. Clinical and laboratory data of anemic patients were obtained at study enrolment. RESULTS: Anemia was diagnosed in 737 of 5416 adult IBD outpatients (prevalence 13.6%); females were more commonly affected than males (odds ratio, 1.5; 95% confidence interval [CI], 1.2-1.7) and had more severe anemia. In the majority of cases, anemia was due to iron deficiency (62.5% of cases; 95% CI, 58.3%-66.6%), either isolated or in association with inflammation and/or vitamin deficiencies; anemia of inflammation accounted for only 8.3% of cases. More severe anemia was associated with increasing fatigue and worse quality of life. Only 68.9% of anemic patients with iron deficiency (95% CI, 63.4%-73.8%) and 34.6% of those with vitamin deficiencies (95% CI, 26.2%-44.2%) were properly treated with supplementation therapy. CONCLUSIONS: In Italy, the prevalence of IBD-associated anemia is lower than previously reported. Anemia of IBD is most commonly due to iron deficiency and contributes to fatigue and poor quality of life, but remains untreated in a large proportion of patients with iron and/or vitamin deficiencies. This study is registered at clinicaltrials.gov as NCT02872376.

The prevalence of inflammatory bowel disease­associated anemia is 13.6%. The prevalence is higher among females younger than 50. Anemia is usually due to iron deficiency and adversely affects fatigue and quality of life. Many patients with iron or vitamin deficiency (31% and 65%, respectively) remain untreated.

Effectiveness of adalimumab for ulcerative colitis: A multicentre, retrospective study of clinical practice in Italy.

BACKGROUND: Adalimumab is used to treat ulcerative colitis, but additional effectiveness and safety data are needed. PATIENTS AND METHODS: This retrospective study considered adults with ulcerative colitis treated with adalimumab at 19 hospitals. Clinical data were collected from the start of treatment, after 2, 6 and 12 months, and at the last visit. Outcome measures of effectiveness were treatment duration, reasons for discontinuation and colectomy. RESULTS: We studied 381 patients treated with adalimumab for a median of 12.1 months. Disease activity at the start of treatment was moderate to severe in 262 cases (68.8%) and endoscopic activity was moderate to severe in 339 cases (89.0%). At week 8, clinical responses were observed in 177 cases (46.5%) and clinical remission in 136 cases (35.7%). At 12 months, remission was observed in 128 cases (33.6%). Overall, 44 patients required colectomy, and 170 patients (44.6%) were still taking adalimumab when data were collected. Variables associated with adalimumab discontinuation were concomitant steroid treatment, severe clinical-endoscopic activity at baseline, need for adalimumab intensification and drug-related adverse events. Variables associated with colectomy were concomitant steroid treatment and high baseline C-reactive protein. CONCLUSION: Adalimumab is safe and effective for the treatment of ulcerative colitis.

Factors associated with disability in patients with ulcerative colitis: A cross-sectional study.

OBJECTIVES: Ulcerative colitis (UC) can give rise to several restrictions of patients' working and social activities. We aimed to determine the association between disease chronicity and the state of disability in a large population with UC. METHODS: We recruited consecutive patients with UC attending the inflammatory bowel disease (IBD) unit of the Azienda Ospedaliera of Padua between July and December 2017. We collected patients' characteristics and clinical information, and all participants completed the IBD questionnaire (IBDQ) for quality of life assessment and the IBD disability index (IBD-DI) questionnaire. Using univariate logistic regression models we assessed whether the patients' characteristics and IBD-related variables were associated with an IBD-DI score ≤3.5. Statistically significant variables in the univariate analyses were then included in a multivariate regression model. Correlations between IBD-DI and all the above mentioned characteristics were investigated using the Spearman's rank correlation coefficient. RESULTS: We included 201 patients. A positive correlation was observed between IBD-DI and IBDQ (r = 0.82, P < 0.001). Multivariate regression modelling identified the following as independent factors related to disability: active disease (partial Mayo score ≥2) (odds ratio [OR] 6.54, 95% CI 3.21-13.22), the presence of extraintestinal manifestations (EIM) (OR 2.48, 95%, CI 1.11-5.54) and occasional alcohol consumption (OR 0.39, 95% CI 0.20-0.76). CONCLUSIONS: Impaired disability is mainly correlated with disease activity, the presence of EIM and no alcohol consumption. Moreover, there is a strong correlation with patients' quality of life. Therefore, in clinical practice, greater awareness of IBD-related disability is needed to better manage patients' outcomes.

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

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.

Relevance of fecal calprotectin and lactoferrin in the post-operative management of inflammatory bowel diseases.

The role of fecal lactoferrin and calprotectin has been extensively studied in many areas of inflammatory bowel disease (IBD) patients' management. The post-operative setting in both Crohn's disease (CD) and ulcerative colitis (UC) patients has been less investigated although few promising results come from small, cross-sectional studies. Therefore, the current post-operative management still requires endoscopy 6-12 mo after intestinal resection for CD in order to exclude endoscopic recurrence and plan the therapeutic strategy. In patients who underwent restorative proctocolectomy, endoscopy is required whenever symptoms includes the possibility of pouchitis. There is emerging evidence that fecal calprotectin and lactoferrin are useful surrogate markers of inflammation in the post-operative setting, they correlate with the presence and severity of endoscopic recurrence according to Rutgeerts' score and possibly predict the subsequent clinical recurrence and response to therapy in CD patients. Similarly, fecal markers show a good correlation with the presence of pouchitis, as confirmed by endoscopy in operated UC patients. Fecal calprotectin seems to be able to predict the short-term development of pouchitis in asymptomatic patients and to vary according to response to medical treatment. The possibility of both fecal markers to used in the routine clinical practice for monitoring IBD patients in the post-operative setting should be confirmed in multicentric clinical trial with large sample set. An algorithm that can predict the optimal use and timing of fecal markers testing, the effective need and timing of endoscopy and the cost-effectiveness of these as a strategy of care would be of great interest.

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.

A nurse-led accelerated procedure for infliximab infusion is well tolerated and effective in patients with inflammatory bowel disease.

BACKGROUND: Shorter infusions of infliximab for inflammatory bowel disease seem to be as tolerated as standard procedures and nurses may be able to manage them safely. AIMS: To test tolerability and effectiveness of a fast nurse-led infusion procedure and the related patients' satisfaction. METHODS: We retrospectively compared three different regimens adopted in our outpatient infusion unit from 2010 to 2013: Group 1, a standard procedure with two-hour infusions, preceded by hydrocortisone medication (87 patients, 311 infusions); Group 2, a similar regimen without physician supervision (130 patients, 464 infusions); Group 3, a one-hour nurse-led procedure without routine premedication (176 patients, 1356 infusions). Disease characteristics, infusion reactions, infusions per month and patients' satisfaction were recorded. RESULTS: There were significantly fewer infusion reactions in Group 3 than Group 1 (2.2% versus 5.8% respectively; p=0.001). The only significant risk factor for side effects was premedication (odds ratio 4.71, 95% confidence interval 2.21-10.02, p<0.001) which was related to the presence of previous side effects. Number of infusions per month increased by 27% (83 versus 61, p<0.001) without increasing nurses' workload and patients were satisfied. CONCLUSIONS: Our fast nurse-led procedure was well tolerated, effective and satisfactory for patients.

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.

Fecal lactoferrin and intestinal permeability are effective non-invasive markers in the diagnostic work-up of chronic diarrhea.

Non-invasive markers able to identify patients with chronic diarrhea at risk of organic disease are missing. Aim of the study was to assess the diagnostic ability of intestinal permeability (IP) test and fecal lactoferrin (FL) in distinguishing functional from organic disease in patients with chronic diarrhea. We retrospectively enrolled patients referring to the gastroenterology outpatient clinic for chronic diarrhea. Among the 103 patients included, 40 % had an organic disease, with IP and FL levels significantly higher compared to those with a functional disorder (p < 0.0001). Sensitivity, specificity, positive and negative likelihood ratios, area under ROC curves of FL were superior to those of IP in discriminating functional and organic disease (FL: 87.8 and 93.6 %, 13.61 and 0.13, 0.9375; IP: 61.0 and 90.3 %, 6.3 and 0.43, 0.7691). When combining the two tests, the diagnostic ability of FL did not improve. In subgroup analysis, IP confirmed its ability to detect small bowel alterations, while FL could identify both small bowel and colonic alterations. In conclusion, FL is valid to detect inflammation in the gastrointestinal tract, while IP can effectively identify small bowel damage in chronic diarrhea patients. Together these tests could recognize both the presence of intestinal damage and its site.

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 Crohn's 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.

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 Crohn's 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. Crohn's 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.

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

Maintenance of medically induced remission is a clinical challenge in Crohn's 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.

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.

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.