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Introduction: Increased intestinal permeability has been reported in inflammatory bowel disease (IBD) patients and is associated with occurrence of relapses [1]. An intestinal barrier function defect is thought to be one of the mechanisms leading to the pathogenesis of IBD development and subsequent flare. Measurement of small-molecular-weight saccharides1, chromium-EDTA or in vitro techniques (trans-epithelial electrical resistance and 3H-mannitol flux) are the methods currently used to evaluate it, but no in vivo evidence of these defects has so far been available. Whether this suggested tight junction dysfunction has a clinical impact also needs to be demonstrated [2].

Introduction: Although identification of a single cytokine responsible for the pathogenesis of a chronic inflammatory condition seems promising for providing targeted curative treatment, this cannot be achieved for inflammatory bowel disease (IBD) with its complex and heterogeneous etiology. However, for a subgroup of IBD patients – children with very early onset IBD – one such cytokine seems to be Interleukin-10 (IL-10), known for its anti-inflammatory properties. First evidence for a role of IL-10 in IBD emerged yet nearly 20 years ago, when IL-10-/- mice had been shown to develop severe enterocolitis (1), an effect that could be reversed by IL-10 gene therapy (2). In 2009, three mutations in genes encoding for the IL-10 receptor (IL10R1 and IL10R2) were identified in children with early onset IBD (3). As a consequence, peripheral blood mononuclear cells (PBMCs) of affected children produced higher amounts of pro-inflammatory cytokines. As a proof of principle, one patient was successfully treated with allogeneic stem-cell transplantation, and sustained remission could be achieved.

Introduction: Cigarette smoke contains hundreds of potentially toxic (or therapeutic) compounds, many of which have unknown action in the human body [1]. Ulcerative colitis (UC) and Crohn’s disease (CD) show an inverse association with cigarette smoking exposure. Non- or ex-smokers have a higher risk for UC while smokers are more likely to suffer from CD. Anecdotal evidence suggested that smoking resumption may improve the clinical outcome of ex-smokers with refractory UC.Cigarette smoking has a negative impact on most autoimmune disorders, being associated with a high risk of cardiovascular, lung and digestive diseases; notwithstanding of this, cigarette smoking appears to have beneficial effects in UC. Studies showed that carbon monoxide (CO) is one candidate that may concur to this helpful effect [3-4]. Nicotine could also be responsible for most of the immunoregulatory effects of cigarette smoke. Also it is worth mentioning that considering the bimodal distribution of UC [5-6], the second older-age peak (between 50 and 80 years of age) is characterized by higher rates of former smokers [7-9], thus suggesting that smoking suspends the onset of the UC rather than fully protecting it.

Introduction:Infliximab (IFX) has dramatically changed the approach to the management of patients with Crohn’s Disease (CD) [1]. IFX induces rapid and profound endoscopic healing, improves quality of life and allows patients to avoid hospitalisation and surgery [2]. The ACCENT I [3] and ACCENT II [4] trials have shown that scheduled maintenance therapy with IFX is superior to episodic therapy in maintaining response and remission both in luminal and in fistulising CD. Nonetheless, approximately 60% of patients cannot reach remission and 25–40% of patients on an IFX maintenance regimen experience a loss of response to the drug [5].
It has been demonstrated that the combination of IFX and azathioprine is more effective than IFX alone in inducing steroid-free remission and mucosal healing of the bowel in luminal CD in patients not treated previously with azathioprine. The Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC) also showed that IFX monotherapy is significantly better at inducing steroid-free remission and mucosal healing than azathioprine alone in azathioprine-naive patients [6].
It is important, however, to determine whether IFX therapy can be safely interrupted in patients with CD who have undergone a period of prolonged remission, and the timing of IFX withdrawal in patients who receive combination therapy is one of the most controversial topics in IBD management.

Introduction: A substantial number of patients with acute severe ulcerative colitis are glucocorticoid resistant. Before cyclosporine (CsA) and infliximab (IFX) were introduced as rescue therapies colectomy rates were 46% at 3 months and 64% at 10 years.(1) Both CsA and IFX are effective in reducing colectomy rates to around 36%.(2;3)
It is not clear whether one of these drugs is superior to the other, although a single infusion of IFX seems less effective than CsA induction therapy. (4) On the other hand, preliminary results of a randomized controlled trial comparing CsA (2 week intravenous (IV) infusion followed by a daily oral formulation) with scheduled IV IFX (Week 0, 2, 6 followed by every 8 weeks) show equal clinical response rates and colectomy rates at 1 and 14 weeks.(5) Long-term data, including data on the role of antimetabolite co-treatment are awaited.

Introduction: The CRP response in Crohn’s disease (CD) is stronger than in ulcerative colitis (UC). For current treatment decisions in Crohn’s disease, the level of C-reactive protein (CRP) is a major biochemical guide. However, CRP and endoscopic findings correlate poorly. The mechanism of CRP production is still poorly understood. Recently, adipocytes were identified as a source of CRP aside the liver. Since CD is characterized by mesenteric fat hyperplasia, the authors focused on the role of mesenteric fat in CRP production and the inflammatory process CD.

Introduction: Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology, but is generally thought to result from the combination of an exaggerated inflammatory response in a genetically susceptible host exposed to an appropriate environmental trigger.[1] Data on the natural history, namely mortality, of CD from population-based studies is, nevertheless, relatively limited. In light of the evidence published so far, the trend is to believe that CD mortality is still higher than that of the background population. An initial meta-analysis (2007), which included 13 papers (including some from referral centers), found that CD patients had a higher mortality than the control population (pooled estimated standardised mortality ratio, SMR = 1.52; 95%CI: 1.32-1.74). However, the authors noticed that the SMR decreased over time, although this decrease was not statistically significant (p = 0.08).[2] In another meta-analysis (2010), including nine population-based studies (eight were European), mortality in CD was increased, with an SMR of 1.39 (95%CI: 1.30-1.49).[3] A further meta-analysis (2012) concluded the same, with an approximate SMR of 1.5 above background population, especially when the patients were diagnosed at a younger age and required multiple or extensive surgical interventions.[4, 5]

Introduction: The incidence of inflammatory bowel disease (IBD) is increasing worldwide. As the worldwide population is ageing, the proportion of elderly onset IBD patients is also on the rise [1, 2]. The management of IBD in this population is complex because of problems with co-morbidities, polypharmacy, impaired mobility and cognition etc. The risk/benefit ratio of medical and surgical therapies should always be taken into account, especially in this fragile population [3, 4]. A better knowledge of the natural history and the further course of the disease at a population-based level could help in making therapeutic decisions, and in improving the quality of care to these patients.

First introduced by Svartz in 1942, 5-aminosalicylates (5-ASAs) are a well-established and effective first-line therapy for the induction and maintenance of remission in patients with mild-to-moderate Ulcerative Colitis (UC). They remain the most frequently prescribed medication for UC and are known to be effective and well tolerated [1]. Between 87% and 98% of UC patients receive 5-ASA treatment within the first year of diagnosis and 60%–87% continue on this treatment at ten years [2, 3].

Escalation to anti-metabolites (thiopurines or methotrexate) and/or biologic or small molecule therapy is often required for UC patients with a more aggressive disease course. Whilst it is now accepted that discontinuing 5-ASA therapy when escalating to a biologic is not associated with adverse outcomes, less is known about the therapeutic benefit of continuation of 5-ASAs with an antimetabolite [2, 4].

Singh et al conducted a retrospective cohort study to evaluate the pattern of 5-ASA use in patients with UC following escalation to an antimetabolite. The study evaluated patients escalated to antimetabolite therapy (stopping 5-ASA vs short-term 5-ASA use for <6 months vs persistent 5-ASA use for >6 months) and compared the risk of clinically important complications based on the pattern of 5-ASA use in these patients. They hypothesised that continuing 5-ASA therapy would not be more beneficial than stopping it.

Introduction: Corticosteroids are effective for inducing rapid remission in active Ulcerative colitis (UC), but due to their adverse effects they are usually reserved for patients who have failed mesalazine, patients who need a prompt response or those with severe disease [1, 2].
Oral budesonide is a topically acting corticosteroid with low bioavailability and few systemic side effects [3, 4] and this local activity in the colonic mucosa is the key to their efficacy. However, current oral pH-modified release formulations of budesonide are able to act only in the distal ileum and proximal colon and so are not optimally designed for anatomical distribution of UC [5]. In fact, a recent study assessed that oral budesonide was significantly less effective than mesalazine for inducing clinical remission in active UC (risk ratio 0.72; 95% CI 0.57 to 0.91) [6]. This lower effect may also be due to the altered intestinal pH of UC patients.
On the other side, the colonic release Multi-Matrix system (MMX) has already been used successfully with oral mesalazine (mesalazine MMX) [7-9]. This technology provides targeted drug delivery to the entire colon, as supported by scintigraphic data [10]. Based on this, the current study assessed whether the use of this technology coupled with budesonide can help to improve the efficacy of corticosteroids while minimizing systemic side effects in UC patients.

Introduction: The conventional thiopurines, azathioprine (AZA) and mercaptopurine (MP), are the cornerstone of immunosupressive maintenance therapy in inflammatory bowel disease (IBD). Unfortunately, up to half of patients have no benefit from this antimetabolite therapy due to lack of efficacy but mainly because intractable side-effects develop (1). The majority of these thiopurine failing patients is subsequently treated in a step-up regime with methotrexate (in Crohn’s disease) or biologicals. The unfavorable outcome of thiopurine administration can in part be explained by the complex metabolism and its generated metabolites (especially the metabolites 6-thioguaninenucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP)). Thiopurine metabolism can be optimized by co-administration of allopurinol (a xanthine oxidase inhibitor, regularly used in the treatment of gout), leading to a striking decrease in 6-MMP levels and mild increase in 6-TGN levels.
Several small scaled studies have demonstrated earlier that low-dose thiopurine (approximately 25-33% of its original weight-based dosage) in combination with allopurinol (100mg/day) can overcome several side effects (especially those associated with high 6-MMP levels, like transaminitis) that developed during regular thiopurine monotherapy. Moreover combination therapy showed good clinical efficacy (2,3). The study by the Sanderson group provides essential data on safety and success in a large real life cohort of 110 IBD patients using this combination therapy with an average follow-up of 16 months.

Therapeutic drug monitoring (TDM) of the anti-TNF monoclonal antibodies, infliximab and adalimumab, in patients with Inflammatory Bowel Disease is gradually being adopted into routine clinical practice in the United Kingdom [1] and United States [2]. The aim of TDM, measuring an individual’s drug and anti-drug antibody levels, is to assess compliance, drug metabolism and immunogenicity with a view to guiding adjustments or changes in management in order to improve clinical outcomes1. TDM can be proactive, with routine measurement of drug level and anti-drug antibody regardless of clinical outcome, or reactive, with measurement of drug level and anti-drug antibody in the setting of loss of response [3]. Compared to empirical dosing alone, TDM used reactively, at the time of loss of response to an anti-TNF treatment, improves durability of response and safety and leads to significant cost savings [4,5]. The evidence base supporting proactive over reactive TDM is, however, less clear. Two randomised controlled trials done in adults (TAXIT [6] and TAILORIX [7]) did not demonstrate any differences in biological, endoscopic or corticosteroid-free remission between groups, though these trials were limited by methodological limitations and isolating the effect of proactive TDM on defined outcomes was difficult. In contrast, multiple observational studies have concluded that there is less risk of treatment failure and relapse, higher rates of drug persistence and better clinical outcomes in patients who undergo proactive TDM compared to reactive TDM [8–11]. The authors aimed to add to this debate by carrying out a pragmatic, randomised controlled trial assessing whether proactive TDM is superior to reactive testing in children with Crohn’s Disease.

The aetiopathogenesis of CD is multifactorial but includes the interaction between the microbiome and the host’s immune response. Up to 80% of patients with Crohn’s Disease (CD) require surgery during their lifetime and many factors are associated with postoperative recurrence (POR). Differential abundance of bacterial species is seen in patients with IBD compared with healthy individuals and several studies have suggested an association between microbiota composition and CD recurrence [1–3]. Altered mucosal gene expression and abundance of specific microbiota are associated with, and specific to, ileal CD [4].

Introduction: In this descriptive retrospective single-centre study, Katsanos and colleagues searched the records of all their IBD patients receiving EPO therapy between 1994 and 2009. The list included 26 IBD patients (16 UC, 10 CD) with particular refractory disease in need of immunomodulators (65%), or infliximab (27%). These subjects were receiving EPO therapy because their anemia was not responding to I.V. iron therapy or because of a poor tolerance, or severe adverse reaction, to I.V. iron therapy. The paper summarizes 15 years of experiences of a single centre with EPO therapy.

Introduction: : Inflammatory bowel disease (IBD) is a well known risk factor for thromboembolic events. There is clear evidence in the literature indicating a significant correlation between coagulation and inflammation in Crohn‘s disease and ulcerative colitis, leading to an increased risk for venous thromboembolism (VTE) 1, 2.
The association between VTE and malignancy has also been recognized and is widely accepted for more than a century now. In recent years, there is increasing evidence that thromboembolic complications commonly occur before a cancer is diagnosed, and that primary VTE might be a useful marker of an occult tumor 3.
In contrast to primary VTE, the role of secondary VTE as a suitable tool to predict the onset of cancer is still unknown. It remains controversial whether thromboembolic complications occurring in patients with secondary VTE (i.e. in patients with known risk factors such as IBD) can also be used as a marker of an occult tumor. A better understanding of the correlation between IBD and VTE is required to clarify the usefulness of detecting hidden cancers in patients with IBD.

Colorectal cancer (CRC) and small bowel adenocarcinoma (SBA) are severe com-plications of inflammatory bowel dis-eases (IBD) and represent a major concern in the follow-up of these patients. The association between CRC and ulcerative colitis has been well established since the first case was described in 1925, whereas conflicting data about the risk of CRC in Crohn’s disease (CD) have been reported in the literature. A strong association between CD and small bowel cancer has been established without any reduction of this risk in recent decades. The risk of CRC in CD is less clear. An increase in risk of about 2.5-fold has been reported in several studies, including two recent meta-analyses, whereas other studies reported no increased risk of CRC in the CD population. The well-established risk factors for CRC in IBD are disease duration, an early age at diagnosis (usually associated with long disease duration), the disease location (colonic loca-tion and extensive disease), a familial history of CRC, concomitant primary sclerosing cholangitis and male gender. Environmental, dietary and genetic factors can influence the risk of CRC and small bowel adenocarcinoma. Geo-graphic variations have been reported, with an increased risk in North America and the United Kingdom.

Introduction: Patients with longstanding ulcerative colitis (UC) and Crohn’s colitis (CD) are at increased risk of developing colorectal cancer (CRC). (1) It is commonly accepted that CRC develops along the inflammation dysplasia carcinoma sequence which is reflected by the fact that extent, severity and duration of colitis are the main risk factors for developing CRC.
Although numerous studies have investigated the risk of CRC in IBD patients, their results show large heterogeneity and therefore there is still debate on whether and to what extent the risk of CRC is increased in patients with IBD. (2) An interesting observation from recently published cohorts is that the CRC risk seems to be declining. (3) A popular hypothesis for this decline in CRC risk is that this is due chemopreventive effects of mesalamine and immunosuppressive agents, although there is no strong evidence to support this. (4, 5)