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The anti-TNF monoclonal antibody infliximab offers an effective treatment for patients with Inflammatory Bowel Disease (IBD) refractory to conventional immunomodulator therapies. Successful biologic therapy can lead to clinical and endoscopic remission as well as reduced hospitalisation and requirement for surgery [1].

Unfortunately, as a large protein and chimeric antibody, infliximab is immunogenic and this frequently leads to formation of anti-drug antibodies (ADA), with subsequent secondary loss of response (LOR), drug discontinuation and adverse reactions [2]. Identifying patients at increased risk of developing antibodies prior to treatment may establish which individuals require closer drug level monitoring, concomitant immunomodulator therapy and observation for adverse events.

Previous work by Sazonovs et al. identified the first genetic locus to be robustly associated with immunogenicity to anti-TNF therapies [3]. The HLADQA1*05 allele variant rs2097432, carried by approximately 40% of Europeans, significantly increased the rate of formation of infliximab ADA. In the study reviewed here, Wilson et al. aimed to independently identify whether presence of the variant allele was associated with increased risk of ADA formation, LOR, drug discontinuation and adverse events.

No increased risk of SBA or CRC was demonstrated in this study despite the long follow-up and the large number of patients. Young age at diagnosis, male gender and stricturing disease at diagnosis were identified as possible risk factors. This suggests that young males with CD should be monitored more carefully from the start, independent of disease location. Studies of colitis in mice as well as clinical trials have suggested that helminth infection can prevent and/or treat IBD.

This article by Broadhurst et al. describes the disease course of a 35-year-old patient diagnosed with severe UC in 2003, refractory to medical treatment. In early 2004, he chose to infect himself with T. trichiura eggs, followed by a completely symptom-free period. In 2008, after deterioration of disease, he chose again to infect himself with T. trichiura eggs, followed by a progressive improvement of the symptoms and histopathological findings. During the whole disease course, the cellular and molecular portrait of changes in the intestinal mucosa was followed with special attention to IL-22, which promotes wound healing and proliferation and Th17 cells.

Introduction: High geographical variability of IBD has been observed [1, 2]. In developed countries, incidence of IBD has markedly increased over 50 years suggesting an influence of environmental factors associated with industrialization and urbanization of societies [3, 4]. In developing countries, trends of incidence of IBD are lacking. It seems however that IBD is going to emerge in countries of previously low or rare disease prevalence. This has been observed also in Asia, as regards to previous hospital-based studies showing an increased number of treated patients. It becomes therefore important to perform further epidemiological studies in countries were diseases are emerging for different reasons. The emergence of IBD in developing countries or regions where IBD prevalence was low or inexistent suggests that the development of IBD may be influenced by changing environmental risk factors. Collecting prospective information on environmental and “modern” lifestyle exposure factors over time in developing countries undergoing rapid socioeconomic changes and westernization would thus provide a unique opportunity to study the role of such risk factors on the etiology of IBD. The conjunction of potential increase of IBD in developing countries with wide background population also calls for anticipation in terms of planning and organization of healthcare resources.

Reflecting the programme of the 2011 ECCO Congress in Dublin there are different lines of current understanding and research. The classical and probably most established investigation line is the role of the adaptive immune system including the role of Th-1 driven inflammation. The more recent but already very dominant area of interest is the role of the microbiota, which is generally accepted to trigger the inflammation in both Crohn’s Disease and Ulcerative Colitis. Another translational research driven achievement of the past years is the acknowledgment of different clinical phenotypes and disease locations, most importantly the understanding that ileal inflammation is likely due to different factors than inflammation in the colon. The newest and – by some – still controversially discussed field is the understanding of host antimicrobial defense and especially the understanding that – at least – different types of IBD are caused by a barrier problem. In the lines of a barrier problem, different mechanisms including NOD2 mutations, stem cell differentiation WNT signaling defects, Autophagy as well as endosomal stress pinpoint to an important role of the small intestinal crypt – epithelial Paneth cell, especially in case of small intestinal disease involvement.

For some time it has been recognised that alterations in the gut bacteria are associated with Inflammatory Bowel Disease. However, it is unclear which is the chicken and which is the egg – does this “dysbiosis” arise due to genetic differences in affected individuals or because of the inflammatory conditions present in the intestine, or is it causative and a prerequisite for disease to develop, and if so how?

Low bone mineral density (BMD) is both prevalent and frequently unrecognised in patients with inflammatory bowel disease (IBD). With osteoporosis occurring at a rate of 10–14% in the IBD population already at a median age of 33–41 years, low BMD can well be considered an extra intestinal manifestation of IBD. Despite this, and the availability of guidelines from the American Gastroenterological Association and the American College of Gastroenterology, testing rates for osteoporosis have been reported to be low in IBD patients [1, 2].

Introduction: The IL-12 family of cytokines plays an important role in the pathogenesis of IBD. It consists of pro-inflammatory cytokines enhancing inflammation by induction of Th1/ Th17 responses, like IL-12 and IL-23, but also of members with an immunosuppressive function, like IL-27 and IL-35.
Interestingly, the IL-12 family consists of heterodimeric cytokines composed of two subunits, some of which are shared amongst family members. IL-27 is composed of EBI3 (Epstein-Barr virus-induced gene 3) and the IL-27p28 subunit, whereas IL-35 is composed of EBI3 and IL-12p35. In contrast to the well-defined function of IL-12 and IL-23 in IBD, the function of IL-27 and IL-35 is still unclear. In particular, functional studies of IL-35 are hampered by the current limitations in our ability to detect it and the fact that knockout of the EBI3 subunit will also affect IL-27 expression and knock-out of the IL-12p35 unit will also affect IL-12 expression.
Wirtz et al. elegantly circumvented this problem by using mice deficient in both EBI3 (lacking both IL-27 and IL-35) and IL-27p28 (lacking only IL-27) to gain insight into the role of IL-35. The differences between the EBI3 and IL-27p28 deficiency were studied in a variety of established mouse colitis models, using state of the art imaging tools, i.e. murine endoscopy and bioluminescence, to assess colonic inflammation in vivo.

The positioning of medical therapies in the management of Crohn’s Disease (CD) continues to be debated [1] whilst surgery is reserved for cases with disease complications or failure of medical therapy.  The LIR!C trial [2] provided evidence for  surgical resection as an alternative to infliximab (IFX) in the management of localised terminal ileitis, a common presentation of CD [3].

Briefly, the LIR!C trial reported quality of life scores (IBDQ) among 143 adult patients with terminal ileitis (<40 cm) who underwent randomisation to IFX induction/maintenance or ileocaecal resection. Patients were recruited from 29 secondary and tertiary Dutch and British centres. Exclusion criteria included non-inflammatory disease, prestenotic dilatation, abscess and previous surgery. Inclusion criteria included failing at least three months of conventional therapy [immunomodulator (IM) and/or corticosteroid (CS)] [2]

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.