Crohn’s disease of the appendix

Although appendectomy is often the first surgical procedure in patients with Crohn's disease (CD), only few data exist on appendiceal CD. The aim of this study was to analyze appendices of CD patients undergoing surgery. We analyzed 149 specimens from consecutive patients with CD who underwent primary right ileocolonic or (sub)total colonic resection. The appendix was present in 90 resection specimens. Histologic findings were compared with those of 180 age and sex matched controls. Thirty-six appendices showed histologic signs of CD (40%): A transmural inflammation was found in 24 cases (67%), and a mucosal inflammation in 12 cases (33%). Histologic hallmarks of mucosal involvement were focal or discontinuous inflammation with crypt distortion and a histiocytic and lymphocytic predominant inflammation. Furthermore, epitheloid granulomas and erosions or ulcers with abundant histiocytes at the lesions base were observed. In comparison to controls luminal obliteration was significantly overrepresented in CD whereas acute phlegmonous appendicitis was underrepresented ( P<0.01). Patients with CD of the appendix showed a more widespread colonic involvement than those without ( P<0.01). This study shows that CD of the appendix exhibits specific histologic features that allow a differentiation from non-CD-associated appendicitis. CD-associated appendicitis is a frequent event, probably signifying a more widespread colonic involvement.     

Targeting IL-23 in Crohn’s disease

ABSTRACT

Introduction: Interleukin (IL)-23, a cytokine produced by antigen presenting cells, targets both T cells and non-T cell types with the downstream effect of enhancing inflammatory pathways. Genome-wide association studies and data from human and mouse models of intestinal inflammation support the pathogenic role of IL-23 in Crohn’s disease (CD), an immune-mediated disorder that can involve any part of the gastrointestinal tract.

Areas covered: This review summarizes the available data on the role of IL-23 in CD and discusses the therapeutic relevance of blocking the function of IL-23 in this disorder.

Expert commentary: The use of biologic drugs, such as anti-TNF and anti-integrins, has largely improved the management of CD patients. However, a significant proportion of CD patients taking these drugs continue to experience symptoms and have inflammation in the gut, thus suggesting a need for new agents, which block other inflammatory signals. Data emerging from trials with IL-23p40 and p19 blockers indicate that IL-23 is a valid therapeutic target. More studies are needed to optimize the therapeutic regimens, ascertain whether selective inhibition of IL-23p19 is more advantageous than blockade of p40, a subunit shared by IL-12 and IL-23, and evaluate the long-term risk of these approaches.     

Recruitment of activated neutrophils correlates with disease severity in adult Crohn’s disease

Neutrophils are detected in inflamed colon in Crohn’s disease (CD). However, whether the frequency and/or activation of circulating or gut tissue neutrophils correlate with endoscopic severity remains to be investigated. A cohort of 73 CD patients was prospectively enrolled according to endoscopic severity and treatment history. Individuals with active disease were stratified using the Montreal classification. Harvey–Bradshaw Index (HBI) and Simple Endoscopic Score for Crohn’s Disease (SES-CD) were performed at the time of ileocolonoscopy. Frequency of neutrophils and their expression of CD66b and CD64 were assessed in paired blood and colonic biopsies using flow cytometry. The percentage of neutrophils increased in inflamed colon and correlated with SES-CD in the entire cohort of patients examined, as well as in the subgroup with inflammatory (B1) active disease. SES-CD further correlated with neutrophil CD66b expression in mucosa but not blood and, conversely, with neutrophil CD64 expression in blood but not mucosa. However, the evaluation of neutrophil activation in mucosa when compared to blood reflected disease activity more clearly. Finally, a neutrophil activation power index (CD66b in mucosa X CD64 in blood) that correlated with SES-CD discriminated between patients with mild and severe disease. In conclusion, the frequency and activation of colonic neutrophils correlated with SES-CD, highlighting that mucosal neutrophils are associated with disease severity in CD.     

Nuclear factor kappa B plays a pivotal role in polyinosinic-polycytidylic acid-induced expression of human β-defensin 2 in intestinal epithelial cells

Intestinal epithelial cells (IECs) play an important role in protecting the intestinal surface from invading pathogens by producing effector molecules. IECs are one of the major sources of human beta-defensin 2 (hBD-2), and can produce it in response to a variety of stimuli. Although IECs express Toll-like receptor 3 (TLR-3) and can respond to its ligand, double-stranded RNA (dsRNA), hBD-2 expression in response to dsRNA has not been elucidated. In the present study, using an artificial analogue of dsRNA, polyinosinic-polycytidylic acid (poly I:C), we investigated whether the human IEC line, HT-29, can produce hBD-2 in response to poly I:C. HT-29 cells can express hBD-2 mRNA only when stimulated with poly I:C. The induction of hBD-2 mRNA expression was observed at 3 h after stimulation and peaked at 12 h of post-stimulation. Pre-incubation of the cells with nuclear factor kappa B (NF-κB)-specific inhibitor, l-1-4'-tosylamino-phenylethyl-chloromethyl ketone (TPCK) and isohelenine abolished the expression of hBD-2. Detection of the poly I:C signal by TLR-3 on the surface of HT-29 cells was revealed by pre-incubating the cells with anti-TLR-3 antibody. The 5'-regulatory region of the hBD-2 gene contains two NF-κB binding sites. A luciferase assay revealed the importance of the proximal NF-κB binding site for poly I:C-induced expression of hBD-2. Among NF-κB subunits, p65 and p50 were activated by poly I:C stimulation and accumulated in the nucleus. Activation of the p65 subunit was investigated further by determining its phosphorylation status, which revealed that poly I:C stimulation resulted in prolonged phosphorylation of p65. These results indicate clearly that NF-κB plays an indispensable role in poly I:C induced hBD-2 expression in HT-29 cells.     

Natalizumab for the treatment of Crohn’s disease

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disorder characterized by immune-mediated destruction of the salivary and lacrimal glands with unknown etiology. Due to recent research utilizing human subjects as well as laboratory animal models, our understanding of the pathophysiological and immunological mechanisms of pSS has made great strides. As a consequence, targeted, immune-based therapies are gaining increased attention as the ideal way to conquer autoimmune diseases like pSS. Currently, however, there is no effective treatment to target specific immunological events or effector immune cells in the pathogenesis of pSS (discussed in other reviews of the current issue). Here, we summarize our current understanding and knowledge of the roles of monocytes/macrophages in the pathogenesis of pSS. Human studies, especially utilizing salivary gland biopsies, demonstrate the infiltration of macrophages and its correlation with disease severity. Moreover, animal model studies have shown the functional involvement of macrophages in promoting the ocular component of pSS.     

Vedolizumab for the treatment of Crohn’s disease

Introduction: Crohn’s disease (CD) is an immune-mediated condition characterized by inflammation of the gut tissue, associated with progressive damage of the affected intestinal tract and possible complications. A treat-to-target approach is strongly advocated, consisting of early and aggressive inflammatory control. However, a great proportion of affected subjects lack response or are intolerant to conventional therapy. Even though the first-line biologic therapy targeting tumor necrosis factor-alfa (TNF-α) is associated with improvement of inflammation in some patients, others do not respond at first or lose response over time. These findings brought about the possibility of different mechanisms being involved in perpetuating the chronic inflammatory state. Novel drugs targeting different inflammatory pathways have been studied in CD, specifically addressed to leucocyte trafficking.

Areas covered: We aim to review the relevant data available in the literature and briefly summarize the efficacy and safety profile of vedolizumab in the treatment of CD.

Expert commentary: Vedolizumab has shown, from pivotal and real-life data, significant clinical benefit among CD patients, in addition to a singular safety profile. Future studies will provide helpful data concerning its use in special situations.     

Treatment of Crohn’s disease with certolizumab pegol

Biologic therapies have revolutionized the treatment of Crohn’s disease (CD). Targeting TNF-α with monoclonal antibodies has changed the therapeutic landscape for tackling refractory and complicated CD. Intravenous use of infliximab, a chimeric monoclonal antibody to TNF-α is, however, limited by the occurrence of adverse events, infusion reactions, infectious complications, aggravation of heart failure, the occurrence of neurological demyelinating conditions and induction of rare malignancies. The incremental development of next-generation TNF-α antibodies and binding proteins through antibody-engineering techniques has followed, with the aim of producing efficacious drugs that are less expensive to produce, have a convenient route of administration and have fewer side effects. Certolizumab pegol (CDP870, Cimzia^®) is an engineered humanized anti-TNF-α antibody Fab´ fragment that minimizes the protein component and is conjugated to polyethylene glycol. Clinical studies have demonstrated efficacy in the treatment of moderate-to-severe active CD. Reported adverse events in the clinical trial program have been largely of mild-to-moderate severity, and occurred at similar frequencies in the active-treatment and placebo groups. Certolizumab pegol will be a useful addition to the armamentarium of biologic agents that can be used for the long-term treatment of CD.     

Reappraisal of antibodies against Saccharomyces cerevisiae (ASCA) as persistent biomarkers in quiescent Crohn’s disease

A clear correlation exists between microbiota and the dysregulation of the immune response in Inflammatory Bowel Diseases (IBD), which comprise Crohn’s disease (CD) and ulcerative colitis (UC). These unbalanced reactions also involve humoral responses, with antibodies against Saccharomyces cerevisiae. Thus, here we aimed to quantify IgA and IgG specific to S. cerevisiae (ASCA) in quiescent CD and UC, to correlate the production of these antibodies with patient’s inflammatory response and disease clinical presentation. Twenty-nine subjects (16?CD and 13 UC) and 45 healthy controls were enrolled in this study and had plasma samples tested for ASCA and cytokines (IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α), besides clinical evaluation. IBD patients had increase IgA and IgG ASCA, especially those with colonic (L2) and fistulizing (B3) CD. Similarly, patients who dropped out the treatment had augmented ASCA, while IgG was reduced in those receiving sulfasalazine treatment. Furthermore, the quiescent CD patients had elevated IL-6 on plasma, especially in the absence of treatment, together with increased counter regulatory response of IL-10. There was a positive correlation between IgA and IgG on CD but not UC, as well as between IgA and TNF in total IBD patients. In addition, the levels of IgG x TNF, IgA x IL-10 and IgG x IL-10 were also correlated in CD, indicating that ASCA production may be influenced by the inflammatory response. Finally, we concluded that ASCA could be pointed as relevant biomarker of CD presentation and residual inflammation, even in clinical remission patients.     

Significant association of strictures and internal fistula formation in Crohn’s disease

Intestinal inflammation in Crohn’s disease (CD) may be complicated by the occurrence of strictures and fistulae. The pathogenesis of fistula formation is unknown. We therefore wanted to determine whether mechanical factors might contribute to the development of fistulae. Furthermore, we tried to define the path of internal fistulae through the muscular layer. For this purpose, surgical resection specimens from 42 consecutive patients with CD were prospectively studied. In gross examination the whole bowel was cut into circumferential cross sections 0.3 cm thick. Abnormal areas were histologically examined. Strictures were found in 38 patients (90.5%), and fistulae were observed in 27 (64.3%) patients. In 11 (40.7%) specimens fistulae were found within a stricture, in 15 (55.6%) at the proximal end, and in 1 (3.7%) no stricture was found. In 7 (25.9%) cases with fistulae, herniated mucosa was found within the muscularis propria or the subserosa. In 7 (25.9%) cases a blood vessel was identified near a fistula traversing the muscularis propria. From these findings we conclude that that mechanical factors may contribute to fistula formation. This is further supported by the fact that fistulae appear to traverse the muscular layer along piercing vessels. Received: 21 January 2000 / Accepted: 7 March 2000     

Certolizumab pegol for the treatment of Crohn’s disease

Certolizumab pegol is a polyethylene glycolated FAb’ fragment of a humanized anti-TNF-α monoclonal antibody. This pegylated molecule binds with circulating TNF-α and forms an inactive complex that is then eliminated from the body. The drug has been shown to be better than placebo in the treatment of Crohn’s disease and maintaining a clinical response in adult patients with moderate-to-severe active disease who have had an inadequate response to conventional therapy, and the treatment of adults with moderately to severely active rheumatoid arthritis. Comparative trials with an active control group are lacking. The most common adverse reactions include abdominal pain, diarrhea, injection site reactions and infection. All necessary live and attenuated vaccines should be given prior to the initiation of certolizumab pegol therapy, patients should be evaluated for TB risk factors and tested for latent TB prior to initiating therapy, and the initiation of therapy should be avoided if the patient has an active infection. Concomitant use with anakinra is not recommended because of the increased risk of serious infections and neutropenia. Therapy should be discontinued if the patient develops a serious infection during therapy.     

Adalimumab for the treatment of pediatric Crohn’s disease

Inflammatory bowel diseases are characterized by a chronic relapsing course, high morbidity and impaired quality of life. Their incidence is rising, and about 25% of cases are diagnosed in pediatric age. Anti-TNF-α antibodies, such as infliximab and adalimumab (ADA), are usually administered in patients refractory to conventional therapies. However, increasing evidence suggests that they can be introduced earlier in the course of the disease, especially in patients with aggressive and extensive disease since diagnosis. ADA is a fully human anti-TNF-α antibody recently approved for pediatric Crohn’s disease not only in patients unresponsive to infliximab, but also as a first-line anti-TNF-α therapy. In this review, we aim to summarize the current knowledge on the use of ADA in pediatric Crohn’s disease and to discuss open issues regarding safety as well as future perspectives.     

Exclusive enteral nutrition and induction of remission of active Crohn’s disease in children

Exclusive enteral nutrition is an effective therapy for the management of active Crohn’s disease, especially in children and adolescents. This therapeutic approach involves the use of a liquid nutritional product with the exclusion of normal diet for a period of many weeks. Although recent studies have helped to delineate some aspects of how exclusive enteral nutrition should be used, there remain many gaps in our understanding. In addition, several recent reports have provided intriguing insights into the mechanisms of this nutritional approach.