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Introduction: Fatigue has long been linked to inflammatory bowel disease (IBD) and is frequently reported by patients. This symptom has been commonly explained as a consequence of chronic inflammation, anaemia, prevalent sleep problems and psychological co-morbidities such as anxiety and depression.

To date, only a few studies have explored fatigue in IBD and those available have largely involved small samples, in particular hospitalised populations, and have focussed on either active or inactive disease only. As part of their ongoing Manitoba IBD cohort study, Graff et al. conducted the first comprehensive investigation on fatigue in IBD. Their sample of 318 participants was representative of the larger local IBD population, with a mean age of 43 years (SD=14.06), an average disease duration of 6.4 years (SD=2.1), 51% of participants having Crohn’s Disease (CD) and 46% having current active disease.

Introduction:There is no known cure for Ulcerative Colitis (UC), but several agents are frequently used for control of inflammation. High doses of corticosteroids (CS) are administered in acute flares of UC and achieve a high response rate, but this success has the trade-off of a higher risk of complications after surgery. The anti-tumour necrosis factor (TNF)-α antibody infliximab (IFX) is now used in both induction and maintenance therapy for moderate to severe UC. The number of UC patients undergoing surgery after treatment with IFX is increasing. It has been hypothesized that IFX treatment may increase the risk of postoperative complications in patients with UC. Recent investigations have tried to assess this dilemma, with conflicting conclusions. A study on a 10-year experience from Belgium concluded that use of CS, but not IFX, increases the risk of early postoperative complications [1]. On the other hand, two large series globally comparing 132 patients who received IFX as a treatment before surgery with 692 who did not, found that IFX was associated with a higher rate of complications post surgery [2,3].

Introduction: The aetiopathogenesis of inflammatory bowel disease (IBD) remains poorly understood. However, recent advances through genome wide association studies implicate both the immune response to the intestinal microbiome and disruption of intestinal epithelial barrier function as factors likely to influence disease development (1). In addition to host composition, environmental factors can influence the microbiome or alter epithelial barrier function; hence pre-morbid diet is an obvious candidate for study in understanding factors which may predispose to, or protect from disease (2,3).
Dietary fibre is a plausible area for study given in vitro evidence that fermentable fibre can play a role in maintaining epithelial barrier function (4). However the complexity of diet, which, in addition to composition of both macro and mirconutrients, is also influenced by socioeconomic and health behaviours, makes study difficult. This study aimed to use a large prospective cohort of patients to examine the role of dietary fibre in the development of IBD.

Introduction: Intestinal epithelial cells (IEC) have the difficult task to protect the host from potentially harmful luminal content and promoting the uptake of water and nutrients. Specialised IEC such as, Paneth cells, are protective cells located at the small intestine in the crypt base. These cells produce anti-microbial substances such as defensins and lysozyme, but also produce growth factors that are indispensable for the intestinal stem cell niche. Highly secretory cells, such as Paneth cells need to be able to cope with high endoplasmic reticulum (ER)-dependent protein production causing chronic ER stress. As such, micro and macro engulfment of intracellular compartments (e.g. autophagy) is part of the ER stress response to protect cells from noxious ER stress levels.
Defects in Paneth cell function, including impeded defensin production and secretion, have been reported in Crohn’s Disease (CD) patients. The mechanisms behind this phenomenon are still largely unknown. However, a recent short report by Thachil et al. in Gastroenterology from January 2012 elegantly shows that this impeded Paneth cell function in CD patients may be due to increased autophagy-related engulfment of the secretory granules, known as crinophagy. This finding further strengthens in the importance of IEC, in particular the Paneth cells, in a normal gut homeostasis.

Introduction: The development of perianal fistulas is a common complication of Crohn’s disease (CD), with a reported cumulative incidence of about 25% after a disease duration of 20 years (1,2). Although a range of medical and surgical options are available today, the treatment of perianal fistulas remains challenging. Achieving complete closure of the fistulous tract is a long process and relapses are common.
Antibiotics such as ciprofloxacin and metronidazole are widely used as first-line therapy for perianal fistulas; however, re-exacerbations are common after discontinuation of this treatment (3). Several trials clearly demonstrated the benefit of anti-TNF for the induction and maintenance of remission in perianal fistulizing disease (4,5,6).
West et al. (7) combined infliximab therapy with ciprofloxacin or placebo for 12 weeks and found a non-significant difference in response to the treatment in favour of the combination group.

Anti-tumour necrosis factor-α (anti-TNF) has historically been the mainstay of biologic therapy in Inflammatory Bowel Disease (IBD). However, of those who initially respond to anti-TNF, almost 50% will suffer secondary loss of response (SLR) over subsequent years [1,2]. This SLR is primarily predicated on suboptimal anti-TNF trough levels, with or without detectable anti-drug antibodies (ADAs) [3]. Furthermore the prospective, observational study by Kennedy et al. demonstrated that suboptimal anti-TNF trough levels at week 14 predicted ADAs, low trough levels and worse clinical outcomes [4]. This risk was mitigated for both infliximab and adalimumab by the use of immunomodulators such as azathioprine. This corroborates the retrospective data from other cohorts showing how the addition of an immunomodulator can restore clinical response and favourable pharmacokinetics [5–7]. Remission rates when switching to a second anti-TNF have been shown to be lower when the reason to withdraw the first anti-TNF is SLR as compared to intolerance (45% vs 61%) [8]. In the event that SLR to anti-TNF is due to immunogenicity, a switch to another anti-TNF is associated with a risk of ADA to this new therapy [9,10]. A number of patients will also be on anti-TNF monotherapy at the time of switching having de-escalated from previous combination therapy. We know that open-ended prescription of anti-TNF with azathioprine is not without additional risk, notably infection and lymphoma [11]. Furthermore, de-escalation to anti-TNF monotherapy after a period of combination therapy has been shown in most studies not to impact on relapse rates (49% monotherapy versus 48% combination therapy) [12]. It is in precisely this important group of patients that Roblin et al. sought to compare the use of azathioprine in combination with a second anti-TNF versus this second anti-TNF as monotherapy. Over a follow-up period of 2 years, the rates of clinical and immunogenic failure, and of adverse events, were compared.

Mucus covers the intestinal epithelium along the entire gastrointestinal tract and is a central part of the intestinal barrier. Enteric mucus contains goblet cellderived mucins, antimicrobial peptides and immunoglobulins and thus forms both a functional and a physical barrier that prevents the translocation of microbial organisms into the intestinal lamina propria [1]. The composition of mucus varies along the intestinal tract and increases in depth towards the distal colon, where an inner, sterile layer adjacent to the epithelium and an outer non-sterile layer can be distinguished [1, 2]. These structural features are dependent on mucins, a family of oligomerising and non-oligomerising heavily O-glycosylated glycoproteins [1, 2].

Introduction:Ulcerative colitis (UC) is a chronic relapsing disease with incomplete understanding of its pathogenesis [1], and, consequently, a currently missing causal therapy which is pressingly needed. In 2006, infliximab, as the first anti-TNF antibody, has extended the therapeutic armamentarium for UC after efficacy was proven in both induction and maintenance therapy [2].
However, due to insufficient long-term response rates in case of maintenance therapy and potentially severe side-effects associated with the use of anti-TNF antibodies, there is still an urgent need for new therapeutic approaches in UC. The ongoing search for new therapeutics beyond anti-TNF based strategies is documented by an abundance of drugs currently being evaluated in a vast number of preclinical and clinical studies3.
Interferon-g-inducible protein-10 (IP-10; CXCL10) is a chemokine which both directly and indirectly participates in inflammatory cell migration (e.g. Th1 and Th17 cells, as well as monocytes) and epithelial cell survival through binding to the G protein-coupled CXCR3 receptor. High IP-10 expression levels were found in colonic biopsies and plasma from patients with active UC as compared to healthy controls. In addition, preclinical in vivo studies demonstrated therapeutic activity of anti-IP10 treatment in several murine models of colitis [4, 5].

Introduction: Crohn`s disease (CD) and ulcerative colitis (UC) are the two main subtypes of inflammatory bowel disease (IBD). Although the etiology of both diseases still remains unsolved, we have seen significant progress concerning new therapies for both diseases within the last years [1,2]. Especially novel therapeutics, such as anti-TNF agents are promising in the therapy of IBD. Unfortunately, only about 2/3 of the patients show initial response to the new therapies. A cross analysis indicates a loss of infliximab response with a mean of 37% with an annual risk for loss of response about 13% per patient-year [3]. Due to this, further and new therapeutic strategies are still needed.
In refractory cases of IBD, hematopoietic stem cell transplantation has successfully been used in a rare number of patients. However, only a limited subgroup of patients seems eligible for this therapy so far due to a quite risky therapy with potential huge side effects [4,5].

Introduction: Acute severe colitis (ASC) is a potentially life-threatening condition with estimated rates of colectomy of up to 40%(1). Patients presenting with ASC should be admitted to the hospital and started on intravenous (iv) corticosteroids(2). However, around 15 to 57% of patients will be refractory to this therapy (3); in those who fail to respond within 3–5 days, or who present with frank deterioration at any earlier point, rescue therapy with either ciclosporin 2 mg/kg or infliximab (IFX) 5 mg/kg is generally considered as an alternative to surgery.
The efficacy of ciclosporin in the treatment of ASC was demonstrated more than 15 years ago. In a small randomised placebo-controlled trial, 9 out of 11 patients treated with 4 mg/kg ciclosporin has a response compared to none of the 9 placebo-treated patients(4). Later on, in a dose-finding trial, ciclosporin doses of 2 mg/kg and 4 mg/kg per day were found to be equivalent (5). IFX was shown to be an effective salvage therapy in patients with steroid-refractory ASC in a pivotal randomised controlled study conducted by Jarnerot et al. In this trial, 67% (14/21) of patients in the placebo-treated group required colectomy by 3 months as compared to 29% (7/24) of those treated with a single dose of infliximab 5 mg/kg (6).
The decision on whether to select ciclosporin or IFX in the setting of steroid-refractory ASC, in the absence of a specific contra-indication to each particular drug, usually depends on centre and physician’s personal experience and patient’s preference. Arguments supporting IFX are its ease of use and better safety profile. Besides that, because patients previously failing azathioprine are more prone to colectomy following initial response to ciclosporin(7), previous thiopurines-failures may be considered better candidates to IFX. In the other hand, arguments favouring ciclosporin are its reported high and rapid response rates, and its short half-life. Ciclosporin clears more rapidly from the circulation than IFX, and therefore some physicians may prefer its use in patients where colectomy is felt to be more imminent, to prevent septic complications.
So far no clear guidance for the choice between both agents was possible due to the lack of comparative trials. In this recently published manuscript, Laharie et al. present the results of the first trial comparing ciclosporin and IFX for ASC.

Introduction: Ulcerative Colitis (UC) is an idiopathic chronic inflammatory disease of the colon with episodes of relapses between remissions. Conventional pharmacological treatment relies on aminosalicylates and immunomodulators (thiopurines), with or without corticosteroids. However, up to 16% of patients do not respond to optimal treatment with thiopurines [1]. The ACT-1 and ACT-2 have demonstrated efficacy of infliximab (IFX) for both induction and maintenance of remission in corticosteroid and/or thiopurine refractory moderate to severe UC. However, respectively 51% and 42% of patients that received IFX in the ACT-1 and ACT-2 trial also received thiopurines. It remains unclear whether the efficacy of thiopurine and IFX in combination is superior to either alone in the treatment of moderate to severe UC [2].

Introduction: Therapy with immunomodulators has no clear affect on disease progression and rate of surgery in Crohn’s disease (CD), although efficiency has been demonstrated long time ago [1,2]. In children the early treatment with azathioprine resulted in reduced need for prednisolone and lower relapse rates [3,4].
The reason for this lack of affect on disease progression might be a delayed prescription of the drug, therefore the aim of the presented study was to evaluate the concept of early azathioprine therapy in adult patients with Crohn’s disease.

Introduction: In terms of the number of investigations into the use of biologics to induce and maintain clinical remission, Ulcerative Colitis (UC) has been a ‘neglected cousin’ to Crohn’s Disease. ACT-1 and ACT-2 [1] assessed the efficacy and safety of infliximab versus conventional treatment in patients with moderately to severely active UC. UC patients in the infliximab arm were more likely to achieve clinical response, remission or mucosal healing at weeks 8, 30 and 54 than those receiving conventional treatment. In addition, maintenance infliximab reduced the risk of colectomy in this UC patient population [2]. Colombel et al. have undertaken a subgroup efficacy analysis of ACT-1 and ACT-2 to evaluate a possible correlation between endoscopy subscores at 8 weeks of treatment with infliximab or placebo and subsequent long-term clinical outcomes at week 54. The outcomes assessed included colectomy rates, commercial infliximab use, symptomatic remission (Mayo Stool Frequency of 0 or 1 and a rectal bleeding subscore of 0), corticosteroid-free symptomatic remission, corticosteroid-free status and sustained mucosal healing. In effect they asked the question: Does the patient’s response at 8 weeks predict what will happen in a year’s time?
ACT-1 and ACT-2 [1] enrolled UC patients with moderately to severely active colitis despite conventional treatment and placed them into one of three arms: placebo, infliximab (5 mg/kg) and infliximab (10 mg/kg). Colombel et al. separated each of these arms into their Mayo endoscopy subscores at week 8.

Introduction: The aetiology of Inflammatory Bowel Disease (IBD) is still incompletely understood. Epidemiological observations may be helpful in identifying the true causative factors of this disease. Historically, the prevalence and incidence of IBD have been higher in developed countries, with a decreasing gradient from North to South gradient and, to a lesser degree, from West to East [1]. However, more recent data demonstrate changes in demography as countries become more developed and immigration increases [2]. Several hypotheses have been put forward to explain these changing demographics, but direct experimental evidence is lacking in most cases [2,3]. Racial and ethnic relations in different populations and immigration studies offer interesting data which reflect a complex interplay between genetic, environmental and behavioural factors [1–3]. Diet, alterations in the bowel microflora, smoking habits and the influence of hormonal status and drugs are viewed as contributing factors in the manifestation of the disease [1,3]. However, these factors may differ for Western and Eastern European countries. In fact, some articles report that the Western-Eastern discrepancy can be merely attributed to a difference in life styles [1].
Understanding the discrepancies between data from populations with different genetic backgrounds and environmental factors may reveal fundamental aspects of IBD pathogenesis [3].
Recent studies from Eastern Europe have reported acute increases in the incidence of IBD in some countries, comparable with Western European incidence rates, whereas in other Eastern European centres, IBD incidence has not been investigated [4,5]. It remains unknown whether these changes represent true increases in IBD incidence, rising awareness of the disease or differences in diagnostic practices.

In the past few years the armamentarium of drugs used to treat Inflammatory Bowel Disease (IBD) has accelerated, with the emergence of new therapies targeting differing immune pathways (ustekinumab and tofacitinib) and lymphocyte trafficking (vedolizumab). Furthermore, a number of promising new drugs are on the horizon (JAK-1 inhibitors, IL23p19 antibodies and S1P inhibitors) [1, 2]. However, as the choice of drugs expands, so the uncertainty over which drug should be selected by the clinician also increases. Drug selection may be determined by a number of factors such as cost, mechanism of delivery (e.g. oral, intravenous or subcutaneous), presence of co-morbidities (such as malignancy or multiple sclerosis) and presence of extraintestinal manifestations. However, no drug is effective in all patients, with between 10% and 40% of patients suffering from primary and secondary loss of response [3–5].

Perianal fistulising Crohn’s Disease is a challenging phenotype affecting more than 20% of patients diagnosed with Crohn’s Disease. It is associated with debilitating symptoms and significant morbidity, with subsequent reduced quality of life and increased disease-related work disability.

Currently treatment remains challenging, incorporating surgical and medical management; the latter is driven largely by biologic agents, specifically anti-tumour necrosis factor (TNF) agents such as adalimumab (ADA) and infliximab (IFX). Whilst ADA and IFX have proven efficacy in inducing and maintaining fistula healing and closure, a significant proportion of patients fail to respond or lose response over time. Increasing evidence suggests that this is in part due to sub-therapeutic drug levels, with or without the presence of antibodies to anti-TNF agents (ATA), with higher target drug levels required for fistula healing compared to mucosal healing in Crohn’s Disease. However, data evaluating the correlation between anti-TNF levels and perianal fistula outcomes, particularly with ADA, remain limited.

The aim of this study was to assess the association between anti-TNF levels and perianal fistula healing and closure with maintenance ADA and IFX therapy.