Mariangela Allocca

Anti-IL-6 treatment for inflammatory bowel diseases: next cytokine, next target.

Inflammatory bowel diseases (IBD) are chronic, relapsing, and destructive inflammatory disorders of the gastrointestinal tract. Both Crohns disease (CD) and ulcerative colitis (UC) seem to arise from an impaired dialog between the environment and gut microbiota in genetically susceptible hosts, leading to an inappropriate immune activation and resulting in the over-production of pro-inflammatory cytokines. IL-6 is a key modulator of inflammatory response. It is a phylogenetically important cytokine with relevance in IBD, as well as in other chronic inflammatory diseases and cancer. Influencing the production of this cytokine can change the balance of effector CD4+ T cell subsets and induce B cell antibody production. Moreover, given IL-6 is mostly produced from innate immune cells such as macrophages, neutrophils and mast cells, it is a strategic bridge between the innate and the adaptive system. Interestingly, IL-6 induced signaling can be primarily seen in a relatively small number of IL-6 responsive cells whereas in a chronic phase of inflammation it is able to activate almost all cells of the body through a process known as trans-signaling. In this review, we discuss the role of IL-6 in chronic inflammation, with particular emphasis on its role in CD and UC, and we explore the potential to develop anti-IL-6 agents for IBD treatment.

Review article: optimal preparation for surgery in Crohn's disease

One‐third of Crohns disease (CD) patients will undergo abdominal surgery within the first 5 years of diagnosis.

Blockade of lymphocyte trafficking in inflammatory bowel diseases therapy: importance of specificity of endothelial target

Inflammatory bowel diseases (IBD) are chronic, relapsing to continuously active inflammatory disorders of the gastrointestinal tract, of potentially destructive nature. So far, the excessive and/or unbalanced immune response has been the target of the majority of the IBD treatments. Despite the increasing use of immunosuppressants and anti-TNF-α inhibitors, about 30% of patients with Crohn’s disease and about one-tenth of patients with ulcerative colitis still require major abdominal surgery at 5–10 years. As a result, new therapeutic approaches are urgently needed. The endothelium has a key role in the development of the inflammation, as it selectively governs the leukocyte trafficking and the influx of leukocytes into the intestinal mucosa. Drugs blocking such crossing, specifically at intestinal level, are going to be a new therapeutic option in IBD.

Commentary: anaemia in inflammatory bowel disease--the most common and ignored extra intestinal manifestation.

We thank Dhaliwal and Nwokolo for their commentary on our paper. 2 They mention that the detected superiority of pantoprazole-Mg over esomeprazole was marginal. We do not agree. While at 8 weeks the rates of complete remission were similar for both products, the symptom relief rate was significantly higher (P = 0.0206) with pantoprazole-Mg. Whether one regards a more than 5.6% difference clinically marginal is, of course, debatable. They also suggest that the difference in the response rates between pantoprazole-Mg and esomeprazole at the end of 8 weeks could be due to an unbalanced distribution of Helicobacter pylori in the study groups. This may be true, but some points should be considered. Helicobacter pylori was not studied in the present series because gastroduodenal lesions were excluded a priori. As such, there was no justification for testing H. pylori. Why should the presence of H. pylori influence only results at 8 weeks and not at 4 weeks, as no differences were observed between the two groups at week 4? In Brazil, the prevalence of H. pylori ranges from 58% to 80% among adults. 4 Therefore, it is reasonable to assume that some patients enrolled in the study were infected by H. pylori. In addition, the distribution of patients, in terms of various demographic features that might have influenced H. pylori prevalence, was similar in the various groups.

Golimumab: clinical update on its use for ulcerative colitis.

Monoclonal antibodies directed against tumor necrosis factor alpha (anti-TNF-α agents) have dramatically changed the therapeutical approach to inflammatory bowel diseases, such as Crohns disease and ulcerative colitis. A new anti-TNF drug, golimumab, has recently been approved for patients with moderate to severe ulcerative colitis. Its efficacy has been demonstrated by preclinical and clinical studies and the drug showed an efficacy and safety profile in line with the other anti-TNF agents, such as infliximab and adalimumab. This review gives an overview on golimumab in the treatment of moderate to severe ulcerative colitis.

Cross-Sectional Imaging Modalities in Crohn's Disease

The standard tools assessing the activity of Crohns disease (CD) measure the severity of symptoms (the Crohns Disease Activity Index) or the degree of endoscopic lesions (the Crohns Disease Endoscopic Index of Severity, the Simplified Endoscopy Score), not the global bowel damage. It is necessary to find new instruments able to assess the structural and functional damage to the intestine and the progression over time. We reviewed recent publications on the accuracy of abdominal ultrasound (US), computed tomography enterography (CTE), and magnetic resonance imaging enterography (MRE) for the assessment of CD. US, CTE and MRE have been shown to have a high and comparable diagnostic accuracy for both the diagnosis and complications of CD, but US and MRE have the major advantage of not imparting ionizing radiation. In summary, findings from these imaging modalities with endoscopic lesions and surgical history incorporating into the Lémann score will allow measuring the global bowel damage at specific time and the progression of disease over time and assessing the impact of different strategies.

Iron deficiency: the hidden miscreant in inflammatory bowel disease.

Iron deficiency (ID) and anemia of chronic diseases (ACD) are the most common causes of anemia in inflammatory bowel disease (IBD), and frequently coexist. In these circumstances, detection of ID may be difficult as inflammation influences the parameters of iron metabolism. The prevalence of iron deficiency anemia (IDA) ranges between 36% and 76% in this population of patients. Anemia may impair physical condition, quality of life (QOL), and cognitive function, negatively affecting almost every aspect of daily life. Furthermore, it may be one of the causes of death in IBD. Consequently, iron replacement therapy should be initiated as soon as ID or IDA is detected, together with the treatment of underlying inflammation. Oral iron therapy is a simple and cheap treatment, but often is poorly tolerated and may worsen the intestinal damage. Moreover, in inflammatory states, duodenal iron absorption is blocked by a cytokine-mediated mechanism. Consequently, intravenous iron therapy is preferred in the presence of severe anemia, intolerance or lack of response to oral iron, and moderately to severely active disease. Recently, new intravenous iron compounds (iron carboxymaltose, iron isomaltoside 1000, ferumoxytol) have become available. Iron carboxymaltose has been shown to be safe and effective in IBD patients with IDA. Furthermore, it allows for rapid administration of high single doses, saving time and costs. If proven to be efficacious and well tolerated, it may become the standard therapy in the near future.

Comparative Accuracy of Bowel Ultrasound Versus Magnetic Resonance Enterography in Combination With Colonoscopy in Assessing Crohn’s Disease and Guiding Clinical Decision-making

Background The comparative accuracy of bowel ultrasound [US] versus magnetic resonance enterography [MRE] in combination with colonoscopy [CS] in assessing Crohns disease [CD] and influencing the decision-making process is unknown. Methods Consecutive ileo-colonic CD patients seen in a tertiary referral centre were prospectively assessed by MRE, CS, and bowel US, within 1 week. Sensitivity, specificity, accuracy, positive predictive value [PPV], and negative predictive value [NPV] of bowel US in assessing localisation, enhancement [presence of vascularisation at Power Doppler], active disease [presence of ulcers at colonoscopy], strictures, fistulas, and abscesses were calculated using CS + MRE findings together as a reference standard. Two blinded inflammatory bowel disease [IBD] specialists reviewed MRE and bowel US findings and were asked to decide the therapeutic strategy [continue versus change therapy]. Kappa agreement with clinical decision was calculated. Results Sixty CD patients [36 with endoscopic disease activity, 28 with complications] were enrolled. For localisation, sensitivity, specificity, accuracy, PPV, and NPV of bowel US were 88%, 96%, 91%, 96%, and 85%, respectively; for enhancement, 87%, 92%, 89%, 93%, and 86%; for activity, 92%, 100%, 96%, 100%, and 94%; for strictures, 75%, 86%, 81%, 78%, and 83%; for fistulas, 100%, 98%, 98%, 66%, and 100%; for abscesses, 100%, 96%, 96%, 33%, and 100%. The concordance of management of CD patients based on bowel US or MRE findings, alone, compared with clinical decision, was 0.768 and 0.767, respectively [p <0.001]. The concordance between bowel US and MRE on management of CD patients was 0.800 [p <0.001]. Conclusions Bowel US is very accurate in assessing CD and is a non-invasive, easy-to-use tool to manage CD patients in clinical practice.

Commentary: antibodies reacting with the infliximab Fab portion – something new?

In their study, Steenholdt et al. retrospectively assessed the association between levels of antibodies reacting with the infliximab (IFX) Fab portion, as determined before IFX exposure, and clinical efficacy at 1 year of IFX maintenance therapy in 29 Crohn’s disease (CD) and 22 ulcerative colitis (UC) patients. Patients with CD in clinical remission at 1 year (n = 8) had lower serum levels of pre-existing IFX antibodies (median 91 mU/L, IQR 61– 228) than patients without clinical remission (n = 21) (median 639 mU/L, IQR 252–1562; P = 0.0014). Moreover, four CD and three UC patients who experienced an infusion reaction to IFX had significantly higher pre-treatment levels of antibodies than patients without reactions. A cut-off value of 439 mU Ab per litre was suggested as being clinically relevant in distinguishing IFX responders from nonresponders with 100% sensitivity and 67% specificity. Anti-animal antibodies can arise from iatrogenic and non-iatrogenic causes. The prevalence of such antibodies largely varies between 1% and 80% depending on the assay used. It has been shown that pre-existing human anti-mouse antibodies can interfere with mouse monoclonal antibody therapy by inactivation of the administered antibody. 8 The retrospective study design, the small number of patients included and, overall, the lack of information on anti-IFX antibodies and IFX trough levels make it difficult to conclusively interpret these results. It is hoped that this study opens new research perspectives other than ATIs and IFX trough levels in the management of therapy with IFX. The identification of a pre-existing IFX antibody cut-off value with a 100% sensitivity, if confirmed by prospective studies and large cohorts, may allow us to identify those patients able to respond to IFX before the initiation of therapy and thus the most appropriate treatment option for each patient.

Accuracy of Humanitas Ultrasound Criteria in Assessing Disease Activity and Severity in Ulcerative Colitis: A Prospective Study

Abstract Background Colonoscopy [CS] is the standard for assessing disease activity in ulcerative colitis [UC], although invasive and poorly tolerated. Bowel ultrasound [BUS] may be a valid alternative in UC patients; however, the comparative accuracy between BUS and CS is unknown. Methods Consecutive patients with UC were prospectively assessed by CS and BUS. Colonic wall thickening [CWT >3 mm], colonic wall flow at power Doppler [CWF], colonic wall pattern [CWP], and presence of lymph nodes evaluated at BUS were compared with CS. The endoscopic activity was assessed according to the Mayo endoscopic sub-score [0–3]. All BUS investigations were performed by two independent gastroenterologists and the kappa statistic for agreement was calculated. Ultrasonography-based criteria (Humanitas Ultrasound Criteria [HUC]) were developed. Results A total of 53 UC patients [56% with left-sided colitis, 19% with pancolitis] were prospectively enrolled. Of these, 22 patients had mucosal healing [Mayo endoscopic sub-score 0–1] and 31 patients were in endoscopic activity. CWT, CWF, hypoechogenic CWP and the presence of lymph nodes significantly correlated with endoscopic activity [p < 0.05]. CWT [p = 0.01] and CWF [p = 0.09] were independent predictors for endoscopic activity. The HUC developed are: [i] the presence of a CWF and CWT > 3 mm; or [ii] the absence of a CWF and CWT > 4.43 mm. They showed high accuracy for the detection of disease activity [sensitivity 0.71, specificity 1.00]. The interobserver agreement for BUS was excellent [kappa 0.86]. Conclusions BUS is a non-invasive, easy-to-use tool to manage UC patients in clinical practice. HUC were very accurate in assessing disease activity in UC patients.