Exabis Library

1. To review the relative benefits and limitations of drug therapy versus dietary intervention for the treatment of IBD 
2. To understand circumstances in which one may consider using drug therapy, dietary intervention or combine the two
3. To consider how treatment paradigms may change in the future to include increased emphasis on the role of dietary interventions

- understand approaches of using Omics-based medicine in other disciplines (oncology)
- review current mainstays in OMICS-based diagnostics
- get an overview of current trial designs on implementing omics into patient care

Combination therapy with infliximab and anti-metabolites is a standard option for patients with Crohn’s disease (CD). The implications of long term use of combination therapy may lead patients and clinicians to contemplate treatment de-escalation once steroid-free remission has been achieved. The aim of our study was to assess the relapse rates and time spent in remission over 2 years, after withdrawal of infliximab or anti-metabolite compared to continuation of combination therapy.

CD patients treated with a combination therapy of infliximab (IFX) and anti-metabolite > 8 months and in sustained steroid-free remission > 6 months were recruited in 64 centers in France, United Kingdom, Belgium, Sweden, Australia, Germany and The Netherlands. Patients were randomized into 3 arms - continuing combination therapy (arm A); stopping IFX (arm B); or stopping anti-metabolite (arm C). In case of a relapse [defined by CDAI and an objective marker of inflammation (CRP or fecal calprotectin)], patients were retreated by resuming infliximab in arm B or the anti-metabolite in arm C, according to a pre-defined scheme, including optimization of IFX up to 10 mg/Kg if necessary in all arms. The two co-primary endpoints were the relapse rate and mean survival time spent in remission over 2 years. A major secondary endpoint was treatment failure (complications or not recapturing remission).

254 patients were screened, 211 randomized, 5 withdrew consent and 1 was lost to follow-up, leaving 205 patients for the analysis - 67 randomized to arm A, 71 to arm B and 67 to arm C. Demographic and clinical characteristics are shown in Table 1. The two-year relapse rates were 14% (IC95%: 4-23%) in arm A, 40% (IC95%: 28-51%) in arm B, and 10% (IC95%: 2-18%) in arm C (p=0.0003 arm B vs arm A and <0.0001 arm B vs arm C) (figure 1). The time spent in remission was 1.91 yrs (IC95%: 1.83-1.99), 1.89 yrs (IC95%: 1.82-1.96) and 1.93 yrs (IC95%: 1.86-2.00) in arm A, B and C, respectively. Out of the 39 relapsers, 28 were retreated/optimized. Remission was achieved in 1/2 retreated patients in arm A, 22/23 in arm B and 2/3 in arm C.  Treatment failure was observed in 4/67, 4/71 and 3/67 patients, in these three arms, respectively. No malignancy was observed, one tuberculosis in arm C and two severe infections (pneumonia and viral pericarditis) in arm B.

Infliximab withdrawal, but not antimetabolite withdrawal, was associated with a significantly higher risk of relapse than continuation of combination therapy.  Almost all patients who stopped IFX achieved rapid remission when resuming treatment. The time spent in remission over 2 years was similar across groups.

Clinical trials with the objective of direct comparison of two or more different therapeutics for the treatment of IBD are rare. Often medication is used without knowing the exact mode of action or one drug is preferred without having evidence for better efficacy. Although budesonide and mesalazine are both often used in the treatment of ulcerative colitis, only three small studies have compared these medications when administered orally. Usually budesonide is administered rectally in distal colitis with very good success, while mesalazine can be delivered orally or rectally.

This paper by Gross et al. provides a direct comparison of orally administered budesonide 9mg once daily (OD) and mesalazine 3g OD in mild-to-moderate ulcerative colitis with the aim of demonstrating non-inferiority of budesonide for inducing clinical remission. 288 patients completed the study. Physician’s Global Assessment and laboratory tests were performed. At baseline and week 8, endoscopy was performed and biopsies were taken to determine endoscopic and histological indices.

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].