# data[].attributes.headline
Dietary Practices and Beliefs in Patients with Inflammatory Bowel Disease

# data[].attributes.subject
Dietary Practices and Beliefs in Patients with Inflammatory Bowel Disease

# data[].attributes.body
The goal of this study was to examine the dietary practices and beliefs of IBD patients. And I just felt this was important because although we have generally accepted dietary recommendations for IBD patients, we don't really talk much about what the patients themselves actually believe about the disease and how much attention they pay to their dietary choices in practice.

This study was conducted by administering a questionnaire that examined the demographics, dietary beliefs, and eating habits in IBD 400 patients. The mean age of the patients was 48.4 years, with 39% having Crohn's disease and 51% having ulcerative colitis.

The most striking part of the findings for me was that almost 50% of the patients had never "received any formal dietary advice, and two-thirds requested for further dietary advice." And I think this is a big deal because if these many patients are not well educated regarding the role of diet in the management of their condition, then it might be more difficult for them to recover because they'll keep making wrong dietary choices. And this ultimately can reduce their quality of life in the long run.

Limdi JK, Aggarwal D, McLaughlin JT. Dietary Practices and Beliefs in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016 Jan;22(1):164-70. doi: 10.1097/MIB.0000000000000585. PMID: 26383912.

# data[].attributes.headline
Environmental Particulate Matter Induces Murine Intestinal Inflammatory Responses and Alters the Gut Microbiome

# data[].attributes.subject
Environmental Particulate Matter Induces Murine Intestinal Inflammatory Responses and Alters the Gut Microbiome

# data[].attributes.body
As we become more conscious of the influence our daily activities have on the environment, it is equally important to assess the impact it can have on our physiology. Particulate matter contains microscopic particles that come from vehicle exhaust, industrial emissions, road dust, cooking, and combustion activities (candles). Particulate matter exposure is associated with an increased risk of Crohn’s disease and hospitalization in patients with inflammatory bowel disease. This study addresses the effects of particulate matter on the gut microbiome, increasing gut permeability. The researchers found that short term exposure of the gut to high levels of particulate matter resulted in increased gut permeability. An individual can develop digestive symptoms such as diarrhea and bloating with a leaky gut. Increased gut permeability will require a change in diet to reduce the symptoms. This study can be used to better understand a patients treatment plan to reduce the onset of gastrointestinal disease by controlling the exposure to airborne particulate matter.

Kish, L., Hotte, N., Kaplan, G. G., Vincent, R., Tso, R., Gänzle, M., Rioux, K. P., Thiesen, A., Barkema, H. W., Wine, E., & Madsen, K. L. (2013). Environmental Particulate Matter Induces Murine Intestinal Inflammatory Responses and Alters the Gut Microbiome. PLoS ONE, 8(4), 1–15.

Clarisa Williams

# data[].attributes.headline
Dramatic Increase in Incidence of Ulcerative Colitis and Crohn's Disease 

# data[].attributes.subject
Dramatic Increase in Incidence of Ulcerative Colitis and Crohn's Disease 

# data[].attributes.body
This study's purpose was to describe the changes in incidence of pediatric inflammatory bowel disease.  Pediatric onset inflammatory disease patients were tracked over 24 years in a population-based study. This study was completed in France between 1988 and 2011. The subjects included different age groups and different digestive locations. There were 1,350 cases followed. The cases included crohn's disease, ulcerative colitis, and inflammatory bowel disease unclassified. This study is important because pediatric-onset IBD can be more aggressive and can lead to pubertal delays and nutritional impairment. The results showed that Crohn's disease and ulcerative colitis incidences increased dramatically in adolescents across the 24 year span. The incidence of inflammatory bowel disease unclassified remained stable until 2000 then the incidence rate dramatically increased. The possible factors listed for the increase of pediatric onset IDC include environmental factors, dietary habits (high protein diet) and antibiotic consumption.

Armengol-Debeir, Laura et al. “Dramatic Increase in Incidence of Ulcerative Colitis and Crohn’s Disease (1988-2011): A Population-Based Study of French Adolescents.” The American journal of gastroenterology 113.2 (2018): 265–272. Web.

Dierra Doaks

# data[].attributes.headline
Tumor necrosis factor and Crohn's disease

# data[].attributes.subject
Tumor necrosis factor and Crohn's disease

# data[].attributes.body
During inflammatory bowel disease (IBD), the production of pro-inflammatory cytokines are increased. Tumor necrosis factor-a (TNF-a) is a particular pro-inflammatory cytokine released during Crohn’s Disease states and it is involved in thrombosis, fibrinolysis, metabolism, inflammation, and apoptotic cell death. The study I attached highlights the benefits of using anti-tnf-a treatment to reverse the disease in patients. In Crohn's disease, TNF-a positive cells can be detected throughout the mucosa, extending into the deep lamina propria.

In this study, TNF-a antibody (cA2) was administered twice to 9 patients and major clinical implications were observed, complete remission. They even saw healing of damaged mucosal layers. They are unsure if this is due to the anti-inflammatory action or immune modulating. This is major as it relates to nutritional sciences because many use nutrition to manage their Crohn’s Disease symptoms and must avoid certain foods.

Van Deventer S. J. (1997). Tumour necrosis factor and Crohn's disease. Gut, 40(4), 443–448. https://doi.org/10.1136/gut.40.4.443

# data[].attributes.headline
Impact of Cigarette Smoking on the Gastrointestinal Tract Inflammation: Opposing Effects in Crohn’s Disease and Ulcerative Colitis

# data[].attributes.subject
Impact of Cigarette Smoking on the Gastrointestinal Tract Inflammation: Opposing Effects in Crohn’s Disease and Ulcerative Colitis

# data[].attributes.body
Joe Devine

This study highlights the reasons behind cigarette smoking being damaging to the GI tract. It shows that nicotine levels in the gastric fluid are significantly higher than in venous and arterial blood. The study also proposes that due to impaired mucosal cell function bacteria infections are more common, which paves the way for more tissue aggravation. Nicotine also acts as a vasoconstrictor, this property alone accounting for reduced blood flow to tissues is a promising avenue of research that would shed light on the inflammatory response of the tissue lining directly linked to smoking.

Berkowitz, L., Schultz, B. M., Salazar, G. A., Pardo-Roa, C., Sebastián, V. P., Álvarez-Lobos, M. M., & Bueno, S. M. (2018). Impact of cigarette smoking on the gastrointestinal tract inflammation: Opposing effects in crohn’s disease and ulcerative colitis. Frontiers in Immunology, 9. https://doi.org/10.3389/fimmu.2018.00074

# data[].attributes.headline
Dietary Inflammatory Potential and Risk of Crohn’s Disease and Ulcerative Colitis

# data[].attributes.subject
Dietary Inflammatory Potential and Risk of Crohn’s Disease and Ulcerative Colitis

# data[].attributes.body
The study I chose is important because it is critical to identify and understand the effect of diet and modifying a diet on the potential risk of Inflammatory bowel diseases (IBD). This study identifies specific dietary patterns and sorts them on a scale from pro-inflammatory to anti-inflammatory by measuring the influence of food groups on inflammatory biomarkers (CRP, IL-6, TNF-α).

The participants who consumed diets higher in pro-inflammatory food groups had a higher risk of developing Crohn’s disease but not ulcerative colitis. While participants that consumed diets lower in pro-inflammatory food groups and higher anti-inflammatory food groups had a significantly lower risk of Crohn’s disease. However, participants who followed a high anti-inflammatory and low pro-inflammatory diet reduced their risk of developing the disease and vice versa; participants who followed a low anti-inflammatory and high pro-inflammatory diet had an increased risk of developing the disease. This strongly relates to nutritional science because it studies the effect of different dietary patterns on disease risk.

Recognizing the influence diet has on IBD risk encourages us to adapt to a high anti-inflammatory and low pro-inflammatory diet, especially those at high risk.

Lo, C. H., Lochhead, P., Khalili, H., Song, M., Tabung, F. K., Burke, K. E., Richter, J. M., Giovannucci, E. L., Chan, A. T., & Ananthakrishnan, A. N. (2020). Dietary Inflammatory Potential and Risk of Crohn's Disease and Ulcerative Colitis. Gastroenterology, 159(3), 873–883.e1. https://doi.org/10.1053/j.gastro.2020.05.011

# data[].attributes.headline
Andrea Ballinger: Treating children with inflammatory bowel disease

# data[].attributes.subject
Andrea Ballinger: Treating children with inflammatory bowel disease

# data[].attributes.body
When treating inflammatory bowel disease in children, it is important to establish remission early, as to encourage normal growth and development. Although, achieving normal growth and development is the goal, this can be hindered by undiagnosed inflammatory bowel disease and poor response to current treatment options. This study is important because it looks at how to alter standardized treatments to better suit children with IBD to net a better treatment response. Additionally, the study looks at how clinicians could use biomarkers to better predict IBD outcomes for pediatric patients. The use of biomarkers would allow for more personalized treatment for patients with high risk of severe IBD versus patients with a milder prognosis, yielding better treatment responses. In addition to biomarker therapy, the study confirmed the use of exclusive enteral nutrition (elimination/reduction of animal fat, dairy, gluten) as a beneficial first line of therapy in children with IBD. Dietary interventions like Exclusive Enteral Nutrition can have a positive effect on the intestinal microbiome and serve as a more nutritionally beneficial alternative to steroids. The use of new, individualized biomarker therapy in addition to standardized dietary changes gives a positive outlook on treatment for children with IBD. As disease onset can be more aggressive in children than adults, having new and more potent treatment options ensures they can continue to develop properly and reach early remission. Clinicians will also have more options on how best to treat patients on an individual basis.

# data[].attributes.attachment_link.readable_text
Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gut characterised by alternating periods of remission and relapse. Whilst the mechanism underlying this disease is yet to be fully understood, old and newer generation treatments can only target selected pathways of this complex inflammatory process. This narrative review aims to provide an update on the most recent advances in treatment of paediatric IBD. A MEDLINE search was conducted using "paediatric inflammatory bowel disease", "paediatric Crohn's disease", "paediatric ulcerative colitis", "treatment", "therapy", "immunosuppressant", "biologic", "monitoring" and "biomarkers" as key words. Clinical trials, systematic reviews, and meta-analyses published between 2014 and 2016 were selected. Studies referring to earlier periods were also considered in case the data was relevant to our scope. Major advances have been achieved in monitoring the individual metabolism, toxicity and response to relevant medications in IBD including thiopurines and biologics. New biologics acting on novel mechanisms such as selective interference with lymphocyte trafficking are emerging treatment options. Current research is investing in the development of reliable prognostic biomarkers, aiming to move towards personalised treatments targeted to individual patients.

Keywords: Paediatric inflammatory bowel disease, Crohn's disease, Ulcerative colitis, Treatment, Therapy, Immunosuppressant, Biologic, Monitoring, Biomarker

Core tip: This narrative review summarises the current practice in treating children with inflammatory bowel disease (IBD) and explores the new advances and future aims. A particular focus of the review are the peculiarities of the paediatric age in respect to the standard practice in adult patients with IBD. Whilst the cause of this condition remains only partly understood, a significant proportion of children does not respond to the treatment options currently available. Developing new treatments is therefore a key target. Major advances have already been achieved in therapeutic drug monitoring.

INTRODUCTION

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gut characterized by alternating periods of remission and relapse[ 1].

It comprises Crohn's disease (CD), ulcerative colitis (UC) and IBD-Unclassified (IBD-U), and its incidence has increased steadily worldwide, particularly in Western countries[ 2- 4]. The disease affects both children and adults, with current estimated prevalence of 2.6 million people in Europe and 1.2 million in North America[ 5]. Approximately 25% of IBD patients are diagnosed before the age of 18[ 6]. Given that a cure for IBD hasn't been developed so far, treatments currently available are mainly aimed to induce and maintain remission. Therapeutic options include corticosteroids which have shown up to 80% efficacy in inducing remission in patients with CD. Other immunomodulators used for the treatment of IBD include thiopurines [ i.e., azathioprine (AZA) and 6-mercaptopurine], methotrexate (MTX) and biological treatments such as anti-tumour necrosis factor (anti-TNFa) therapies like infliximab (IFX) and adalimumab (ADA)[ 5].

CD is characterized by focal, patchy, transmural and granulomatous inflammation and it can affect any part of the intestinal tract as well as extra-intestinal tissue[ 4]. Peak age of diagnosis of CD is between 12 and 25[ 7].

Due to its typical onset in the young age and to the chronicity of the disease, medical treatment remains the cornerstone in CD, with most patients requiring lifelong therapy[ 4]. Whilst for CD surgery is generally an option restricted to patients resistant to maximised medical treatments or with specific complications, approximately 75% of patients with CD will eventually undergo surgical resection[ 4, 8]. Nevertheless, according to the current epidemiology data available, up to 73% of these patients will experience endoscopic recurrence of disease at one year post surgery and 22% to 55% will have a clinical relapse at five years[ 8].

UC mainly involves the large bowel mucosa, with inflammation extending proximally from the rectum in a continuous fashion. In approximately 80% of children, the disease extent is proximal to the splenic flexure, whereas in adults it's more frequently left sided. Prolonged severe inflammation of the colonic mucosa is a known risk factor for the development of colorectal carcinoma[ 9].

Currently, proven medical treatment of paediatric UC is limited to a few options, including amino-salicylates, corticosteroids and thiopurines. More recently, anti-TNF agents have been established for the management of patients with UC who are refractory to conventional medical treatment[ 10]. Choice of therapy is mainly based on disease extension and severity of inflammation. Up to 25% of the total patients with UC currently require a colectomy because of ongoing, severe inflammation, unresponsive to medical therapy, or when the disease is steroid-dependent[ 11].

When a child is diagnosed with IBD, achieving early remission has a positive impact on normal child growth and development, long-term remission and quality of life, thus reducing the psychological burden[ 2]. Children tend to present with a more aggressive course of IBD, therefore immunomodulators and biological treatments are used extensively[ 2].

Whilst an early diagnosis is pivotal to minimize growth deficiency, the signs of CD onset vary and can easily go unnoticed, causing growth deficiency and pubertal delay to precede the intestinal manifestations of the disease[ 12].

The pharmacokinetics (PK) and pharmacodynamics of drugs in children are different from those in adults and the approach to paediatric drug dosing needs to be based on the physiological characteristics of the child and the pharmacokinetic parameters of the drug[ 13].

IBD may develop from a chain of events involving alteration in the microbiome, increase in intestinal permeability leading to bacterial translocation, and subsequent activation of the adaptive immune response to cause tissue damage (a model known as "bacterial penetration cycle hypothesis")[ 15].

As a result of the uncontrolled activation of the mucosal immune system, the pro-inflammatory cytokines released cause chronic inflammation of the gastrointestinal tract[ 5]. In consideration of the crucial role played by cytokines in the development of intestinal inflammation, all current treatments for IBD target downstream events in the host inflammatory response[ 15].

Given the complexity and heterogeneity of IBD, a holy grail of current research is to be able to customize therapy to a patient's predictive biomarker profile, in order to personalise treatment and to maximise response[ 11].

Studies in adult patients with CD have shown that treatments capable of inducing and maintaining endoscopic mucosal healing (MH) have a positive impact on the disease course, by reducing the number of clinical relapses, hospitalizations and surgical interventions[ 16]. Therefore, the current aim in the care of IBD for all ages is achieving intestinal MH, i.e., beyond the simple resolution of symptoms[ 3].

Based on this evidence, the strategy of early introduction of immunomodulators and biological therapies ("top-down") to induce deep remission (long-term intestinal healing) is increasingly used in high-risk paediatric patients ( e.g., children with extensive disease distribution, severe perianal disease, no response to standard medical options, growth retardation and delayed puberty) as an attempt to modify the clinical course of the disease by inducing and maintaining remission, reducing hospitalizations, surgeries, use of corticosteroids, as well as promoting growth and pubertal development[ 3].

Based on the recommendations above, the conventional "step up" approach for paediatric CD, based on amino-salicylates, corticosteroids, and immunomodulators, is increasingly outdated for patients at high risk of complicated disease[ 17, 18].

This narrative review aims to summarise the most recent advances in treating children with IBD and to provide with an overview of the new treatments in this field.

LITERATURE SEARCH

A Medline search using the keywords "paediatric inflammatory bowel disease", "paediatric Crohn's disease", "paediatric ulcerative colitis", "treatment", "therapy", "immunosuppressant", "biologic", "monitoring" and "biomarkers" was carried out.

Retrospective and prospective clinical studies, systematic reviews and meta-analyses published between 2014 and 2016 were selected for this narrative review. Studies conducted earlier were also taken into consideration whenever the data outline was considered relevant to the scope of the review.

DIET, MICROBIOTA AND FAECAL TRANSPLANT

Diet has an impact on the composition of the intestinal microbiome and gut immune status and currently there is growing evidence that the microbiota has a relevant role in the pathogenesis of IBD[ 15].

"Dysbiosis", an imbalanced intestinal microbiota with pro-inflammatory microorganisms prevailing on the protecting ones, has been repeatedly reported in patients with IBD[ 19].

Dietary interventions in children with active CD have proved evidence of a link between diet and the disease[ 15]. Exclusive enteral nutrition (EEN) using a polymeric formula for 6-8 wk, is the first-line therapy to induce remission in children with active CD[ 20, 21]. EEN is effective in inducing remission in approximately 80% of patients, with a clinical remission rate similar to corticosteroids[ 3]. However, as opposed to steroids, EEN provides significant nutritional benefit and is superior in achieving MH[ 3].

EEN also leads to early MH, and long-term benefits of EEN-induced MH are currently being looked into[ 16]. Grover et al[ 16] conducted a prospective cohort study on 54 children with new diagnosis of CD, to evaluate the impact of early EEN-induced MH on predicting sustained remission (SR) on immunomodulators, without need for additional therapy like steroids, biologics or surgery. Paediatric CD Activity Index (PCDAI), C-reactive protein (CRP) and endoscopic assessment at diagnosis were paired with those post 6 wk of EEN. Complete MH was observed in 33%, and near complete in 19%. SR was superior in children with complete MH vs those with active endoscopic disease at 1, 3 and 5 years of follow-up, therefore the authors conclude that following induction of remission with EEN, complete MH is superior to clinical and biochemical remission in predicting SR over and beyond 3 years on maintenance immunomodulators[ 16] (Table ).

Table 1

Mean age 16.1 ± 5.6 yr

Response in 37 (78.7%)

Remission in 33 (70.2%)

Active CD (PCDAI > 7.5 or Harvey-Bradshaw Index ≥ 4)

Decrease in CRP and ESR

Normalisation of CRP in 70% of patients entering remission

Age < 16

Clinical remission (PCDAI < 10) in 45/54 (83%)

At least 6 wk EEN

Biochemical remission (PCDAI < 10, CRP < 5) in 39/54 (72%)

Complete MH in 18/54 (33%)

Nearly complete MH in 10/54 (19%)

SR superior in children with MH vs active endoscopic disease:

P 0.003 at 1 yr

P 0.008 at 2 yr

P 0.005 at 3 yr

Thiopurines

The effect of NAT1 on TGN persists even 1 mo after the interruption of the aminosalicylate

No effect of the NAT2 polymorphism was observed

Biologics and biosimilars

Phase-3, randomized,

Higher body weight, baseline CRP, lower albumin, previous treatment with anti-TNF and presence of anti-IFX antibody were associated with increased ADA clearance

Multicentre, double-blind

Combination of biologics + immunomodulators was more effective than biological monotherapy

MH predicts a better disease course

Improvement of mucosal lesions at 2 yr follow-up was predictive of favourable outcomes

Clinical benefit: 19 (70%) measured by the physical global assessment score

Significant decrease in CRP in children responding to ADA (9 vs 15 mg/L)

Cumulative probability of failure to ADA treatment:

38% at 6 mo, 55% at 1 yr

Primary failure: 8 (30%)

Secondary failure: 5 (26%)

Adverse effects: 11 (40%)

Frymoyer et al[ 38] J Pediatr Gastroenterol Nutr 2016

Monte Carlo simulation analysis constructed using a published population pharmacokinetic model based on data from 112 children in the REACH trial

1000 simulated children

Trough IFX concentration > 3 mg/mL was achieved at week 14 in 21% for albumin level of 3 g/dL vs 41% for albumin of 4 g/dL

Standard IFX maintenance dosing in children with CD is predicted to frequently result in inadequate exposure, especially when albumin levels are low.

Primary non-responders: 6% (13/207)

Severe adverse events: 12% (69/599)

6/19 (31.6%) at week 6

11/19 (57.9%) at week 22

Steroid-free remission in 1/20 (5%) at week 6, 3/20 (15%) at week 14 and 4/20 (20%) at week 22.

Week 22 remission rates:

100% anti-TNF naïve vs 45% anti-TNF exposed

Children were switched from IFX originator to its biosimilar

57% for UC

All patients had PCDAI ≥ 25 at the time of switching

Thalidomide

Lazzerini et al[ 49] JAMA 2013

Double-blind, placebo-controlled, randomized clinical trial

56 padiatric patients with active CD, randomised to receive either thalidomide or placebo

Clinical remission achieved by 13/28 (46.4%) of the children treated with thalidomide vs 3/26 (11.5%) of those who received placebo ( P = 0.01)

Thalidomide compared with placebo resulted in improved clinical remission at 8 wk of treatment and longer-term maintenance of remission.

Almost all had not responded to thiopurines and 35% had not responded to biologics

Responses were not different at 4 wk, but greater improvement was observed at 8 wk in the thalidomide group [75% response in 13/28 (46.4%)] vs 3/26 (11.5%)( P 0.01)

Of the non-responders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 ( P = 0.01).

Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission

Mean duration of clinical remission in the thalidomide group was 181.1 wk vs 6.3 wk in the placebo group ( P < 0.001).

Lazzerini et al[ 50] Inflamm Bowel Dis 2015

Multicenter, double-blind, placebo-controlled, randomized clinical trial

26 paediatric patients with active UC, randomised to receive thalidomide or placebo

Clinical remission at week in 10/12 (83.3%) of the children treated with thalidomide vs 2/11 (18.8%) of those who received placebo ( P = 0.005)

Thalidomide compared with placebo resulted in improved clinical remission at 8 wk of treatment and in longer term maintenance of remission.

All patients had had thiopurines and 35% had received prior IFX treatment

Of the non-responders to placebo who were switched to thalidomide, 8 of 11 (72.7%) subsequently reached remission at week 8 ( P = 0.01)

Clinical remission in the thalidomide group was 135 wk compared with 8 wk in the placebo group ( P < 0.0001).

New treatments

2. observational study at a separate site

Patients with high colonic integrin aE expression showed greater benefit

GZMA is a promising biomarker for etrolizumab response

GZMA expression was different post-treatment

16% of patients who received 1 mg of Ozanimod vs 14% who received 0.5 mg vs 6% of those who received placebo

Clinical remission t 32 wk:

Drop in absolute lymphocyte count at week 8:

49% from baseline in the group who received 1 mg of Ozanimod

32% from baseline in the group who received 0.5 mg

Randomised, double-blind, parallel group trial

78 adult patients with CD

No significant difference in change in CDAI from baseline to week 4, between NKG2D group and placebo group

A single s.c. dose of 2 mg/kg anti-NKG2D did not reduce disease activity at week 4 vs placebo, but the difference was significant at week 12

Age 18-75

Significant difference in change in CDAI at week 12 (delta CDAI -55, P ≤ 0.1) between NKG2D group and placebo group

Disease duration ≥ 3 mo

Significant improvement noted in the non-failure to biologic subgroup treated with anti-NKG2D from week 1

CDAI 220-450

Endoscopic evidence of inflammation

Partial enteral nutrition with allowance of free diet hasn't been proved effective yet. It is unclear whether this depends on the supply of specific nutrients within the polymeric formula or on the exclusion of dietary factors during the course of exclusive polymeric diet[ 15].

Recent studies have aimed to evaluate which of the excluded dietary components in EEN may be responsible for the effect, in order to look into ways to allow a safe whole food diet[ 15].

Sigall-Boneh et al[ 15] validated a dietary intervention that allows whole foods but reduces exposure to dietary components that have been shown to induce inflammation, affect the microbiome and the mucous layer, increase gut permeability or the adherence and translocation of bacteria in mouse or cell line models. They recruited 47 patients including 34 children and 13 young adults with active disease, who were treated with a 6-wk exclusion diet that allowed access to specific foods and up to 50% of dietary calories from a polymeric formula.

So far, efficacy of microbiome-based therapies like probiotics or antibiotics has been limited in IBD[ 19]. Nevertheless, the recent focus on dysbiosis as a plausible key factor in IBD pathogenesis, has led to a growing interest in faecal microbiota transplantation (FMT) as a novel potential treatment option in IBD.

FMT is the administration of faecal material from a donor into the intestinal tract of a recipient, with the aim to change the microbiota composition and restore mucosal health. Over the past few years, FMT has been used successfully for the treatment of recurrent Clostridium difficile infection (CDI) (efficacy of 80%-95%), and is now being evaluated in other diseases possibly driven by the microbiota, including IBD[ 19].

The success rate of FMT in treating UC has been much more limited (clinical remission in 35%) in respect to its success in treating recurrent CDI. However, studies so far have been small and heterogeneous, therefore clear conclusions are difficult to make[ 19].

Even less data is available for FMT in CD, with only isolated cases or heterogeneous small series reporting overall clinical remission in 60%-75%[ 19].

At present, evidence on FMT in IBD is not strong enough to recommend its use as part of routine treatment. Preliminary results are promising and more studies are needed to define the best indications, optimal timing, frequency, mode of delivery, and the most appropriate donor for each patient[ 19].

AMINOSALYCILATES

5-aminosalicylic acid (mesalazine, 5-ASA) acts topically on the gastrointestinal mucosa, with minimal systemic effect. Even though its exact mechanism of action is yet to be understood in its complexity, the pathways that are known to be involved include the blockade of IL-1 production and TNF-α receptor, the inhibition of cyclooxygenase and 5-lipoxygenase, and the blockade of the pro-inflammatory prostaglandin E2 and leukotrienes. On top of the inhibition of multiple inflammatory pathways and the suppression of the nuclear factor kappa B as a main result, amino-salicylates also possess potent anti-oxidant and free-radical-scavenger properties[ 4]. Amino-salicylates are mainly used in the induction and maintenance of remission in UC[ 23].

In CD, their use is no longer recommended in view of limited efficacy. However, there are studies suggesting a possible role in the postoperative maintenance of remission, as well as in the subgroup of children with mild, localised ileal disease. In addition, adult studies suggest a protective role of 5-ASA in IBD against colon cancer in patients with colonic location[ 23].

Given that sulfasalazine is not tolerated in 30%-40% of patients, particularly slow acetylators, the use of its therapeutically active component 5-ASA has led to the development of new formulations, that deliver higher concentrations of 5-ASA without the dose-limiting side effects of sulfasalazine. A wide range of these formulations is available and comprises pH-dependent release coated drugs (targeting the ileum), time-dependent release micro-granules enclosed within a semi-permeable membrane of ethyl-cellulose (released in the whole small and large intestine), and azo-bonded formulations released throughout the colon[ 4].

CORTICOSTEROIDS

The mechanism of action of corticosteroids consists in inhibiting protein synthesis and transcription, which ultimately results in down-regulation of pro-inflammatory cytokines, such as NF-kappa B, TNF-α, interleukin-1 and interleukin-6[ 9].

Clinical remission rates for CD are up to 80%, similarly to EEN, whereas MH rates are significantly lower[ 3]. Corticosteroids improve rapidly and effectively the signs and symptoms of disease in CD, however they are ineffective, and inappropriate, for maintenance therapy[ 17].

In children with moderate-severe active luminal CD, oral prednisolone is given at 1 mg/kg, with a maximum of 40 mg/d, followed by a weaning course over 8-10 wk. Intravenous steroids may be initially needed for severe disease and include methylprednisolone (1-1.5 mg/kg, maximum: 60 mg/d) and hydrocortisone (2-4 mg/kg per dose, maximum 100 mg/dose, four times a day)[ 3].

Adverse effects like adrenal suppression, growth failure, cosmetic and behavioural effects, are dependent on dose and duration[ 3].

Budesonide (maximum of 12 mg/d, followed by weaning course over 2-4 wk) is a topically acting corticosteroid with high first pass hepatic metabolism, which reduces the likelihood of adverse effects[ 3, 9].

Budesonide is particularly recommended for patients with mild to moderate CD involving the distal ileum and/or right colon, as it has been shown to be non-inferior to conventional oral steroids for inducing remission in this specific group. It has also proved to be an effective therapeutic option as enema formulation for distal UC[ 9].

There are currently three formulations of budesonide: two standard formulations including a controlled-release capsule and a pH-dependent capsule both designed to target the ileum and right colon; and a more recent Budesonide-MMX ® capsule that releases the drug throughout the entire colon[ 9].

THIOPURINES

Thiopurines are purine analogues used for the maintenance of disease remission in patients with CD and UC; they include the prodrug AZA and the antimetabolite 6-MP[ 25, 26].

AZA is non-enzymatically degraded to 6-MP which is then metabolised to its active component, 6-thioguanine nucleotide (6-TGN)[ 8]. 6-TGN inhibits the proliferation of T and B lymphocytes, which results in a decrease in the numbers of cytotoxic T cells and plasma cells[ 8].

These dugs are able to block the rapid cell proliferation involved in inflammatory processes, which results in immunosuppression[ 26].

For the treatment of IBD, thiopurines are used at relatively low dosages, so their anti-inflammatory effect is mainly produced by the inhibition of the small GTPase Rac1, leading to apoptosis of activated T-lymphocytes. When given at higher dosages, as in oncological treatments, thiopurines mainly inhibit DNA synthesis[ 26].

Thiopurines are steroid sparing agents and have been proven effective maintenance treatment in paediatric IBD: studies have shown significantly lower cumulative steroid doses and relapse rates at 18 mo in children on 6-MP compared with placebo (9% vs 47%) as well as a reduced need for surgery in CD[ 3, 23]. Recommended doses are 1.0 to 2.5 mg/kg per day for AZA and 1 mg/d for 6-MP[ 25].

Thiopurines are also used effectively to maintain surgically-induced remission in CD, even though a systematic review by Gordon et al[ 8] pointed out that the results for efficacy outcomes between thiopurines and 5-ASA in this group of patients are uncertain.

Testing the activity of the enzyme thiopurine-S-methyltransferase (TPMT) is recommended to guide thiopurine dosing avoiding adverse events[ 26].

Genetic polymorphisms in the TPMT gene are associated with a reduced enzymatic activity and an increased production of the active metabolites TGNs[ 23].

A large prospective study with 1000 individuals established TPMT activity reference intervals, with normal activity associated with a level ≥ 25 nmol/h per gram Hgb[ 27].

According to the current data available, 1 in 300 patients have a very low to absent TPMT activity (homozygous mutant TPMT), 11% have intermediate TPMT activity (heterozygous) and 89% have normal to elevated activity (homozygous wild type TPMT)[ 27].

The use of thiopurines is limited by an extensive spectrum of adverse events in up to almost half of patients, particularly within the first twelve months of treatment. Adverse effects include myelotoxicity, hepatotoxicity, pancreatitis and gastrointestinal complaints[ 26].

Measuring TPMT activity levels (phenotype) or determining TPMT genotype before initiating thiopurine therapy, is recommended by the FDA to limit the likelihood of side effects[ 27]. However, it still remains possible to develop significant myelotoxicity despite normal TPMT activity.

The use of TPMT activity and 6-TGN level monitoring has the potential to avoid nearly a quarter of episodes of myelosuppression[ 27]. In addition, 6-TGN monitoring is helpful to detect non-compliance, under-dosing, and drug resistance or refractory states[ 27].

Blood levels of thiopurine metabolites correlate with the efficacy and toxicity of these drugs as follows: TGN levels higher than 235 pmol/8 × 10 ⁸ red blood cells reflect an adequate therapeutic level, whereas methyl mercaptopurine nucleotides levels above 5700 pmol/8 × 10 ⁸ red blood cells are indicative of hepatotoxicity[ 23].

AZA or 6-MP can be started at the full recommended dose of 2-2.5 mg/kg per day or 1-1.5 mg/kg per day, respectively, in patients with normal to high TPMT activity level. Patients with an intermediate TPMT activity should start, instead, with a daily dose reduced by 30%-70%. Alternative therapy should be offered to individuals with low or absent TPMT activity, or they should be started at 10% of the suggested dosing, given three times per week[ 27].

The results of a recent retrospective study by Benmassaoud et al[ 27] evaluating the safety and efficacy of starting thiopurines at low dose vs full dose in adult patients with CD and normal TPMT, suggest that AZA should be started on full dose in patients with normal TPMT, rather than starting on a lower dose and increasing slowly. This is mainly due to the fact that patients with normal TPMT level may still be exposed to side effects that are unrelated to the enzymatic activity[ 27]. Overall, almost half of the adults treated with thiopurines discontinue their treatment due to ineffectiveness or intolerance[ 26]. It has been hypothesized that prescribing thioguanine (TG) therapy instead of AZA/6-MP reduces the release of potentially toxic metabolites, as its metabolism is less complex with a more direct conversion to the therapeutically active metabolite 6-TGN[ 1].

An increase in mean TGN blood levels has been reported in patients on concomitant treatment with thiopurines and 5-ASA. Moreover, a higher rate of myelotoxicity was observed in this group of patients compared with those treated with the thiopurine alone[ 22]. A plausible explanation comes from in vitro studies showing that amino-salicylates and their metabolites can inhibit the activity of TPMT, even though this observation has not been yet replicated in vivo[ 23].

The enzymes N-acetyltransferases (NAT1 and NAT2, EC 2.3.1.5) are responsible for the N-acetylation of multiple drugs including the amino-salicylates. Subjects are classified as rapid, intermediate or slow acetylators based on the activity of NAT1 and NAT2 that is genetically determined[ 23].

MTX

MTX, a dihydrofolate reductase inhibitor, has long been used effectively to treat rheumatoid arthritis until it was brought into the field of IBD to treat patients with refractory CD. Nowadays, it has become one of the principal alternatives to thiopurines as maintenance treatment[ 28, 29].

Efficacy of MTX, given at 15 mg/m ² once a week for a maximum of 25 mg/wk subcutaneously, is reported as 50%-80% by retrospective cohort studies in children who failed to respond or were intolerant to thiopurines[ 3]. MTX is a first-line treatment option in patients who have concomitant inflammatory arthritis and it represents a valuable alternative to maintenance treatment with anti-TNF[ 3, 29]. Adverse events associated with MTX include flu-like symptoms, transaminitis and, less frequently, myelosuppression, which may require dosage adjustment or drug withdrawal[ 3]. Nausea and vomiting have been reported in 11%-24% of patients, the majority of whom respond to antiemetic medication. Significant hepatocellular liver disease is rare. Contraception is essential[ 3].

Systematic reviews performed by MacDonald JW and by Patel et al[ 29] to assess the efficacy and safety of MTX for the treatment of active refractory CD in adults, show that intramuscular MTX is effective in inducing remission and acts as a steroid sparing agent allowing complete withdrawal from steroids[ 28, 30, 31]. Lower dose oral MTX does not appear to provide any significant benefit in respect to placebo or active comparator[ 28, 31- 33]. Though limited by the small size of the studies analysed, this review could not identify any additional benefit from combining MTX and IFX over IFX monotherapy[ 28, 31].

BIOLOGICS AND BIOSIMILARS

TNF is produced by macrophages, adipocytes, fibroblasts and T cells and acts as a pleiotropic, pro-inflammatory cytokine by triggering a cascade of events that lead to tissue damage[ 5, 7].

IFX, ADA and other anti-TNF agents act by suppressing downstream pathways mediated by TNF including angiogenesis, increase in T-helper cell 1 (Th1) cytokine production (interleukin-12 and interferon-γ), death of intestinal epithelial cells and T-cell resistance to apoptosis[ 5].

IFX

IFX is a chimeric monoclonal antibody and was the first biologic approved for the treatment of moderate to severe paediatric CD[ 34]. The advent of biological therapies has drastically modified the treatment strategies and disease course of IBD in children and the role of IFX and ADA in the management of paediatric IBD was recently updated in the Consensus guidelines of ECCO/ESPGHAN[ 6]. In CD, anti-TNF therapies are currently well established in moderate to severe disease with lack of response to conventional therapy including corticosteroids and immunomodulators, or with contraindications or intolerance to it[ 34]. Anti-TNF agents are also used as a primary induction option for children with active perianal fistulising disease, in combination with targeted surgical intervention, as well as in children at risk of poor outcomes (top-down treatment)[ 3, 20]. One year response and remission rates for IFX in luminal disease are reported as up to 90% and 55%-60% respectively[ 35, 36]. Repeated administration of IFX can lead to immunogenicity in some patients, with possible loss of efficacy and delayed-type hypersensitivity[ 34]. A low proportion of children with CD (10%-25%) are primary anti-TNF non-responders, i.e., they fail to respond after the 6 wk induction course. More commonly, however, the formation of antibody against the drug over time can result in secondary loss of response. Concomitant treatment with either thiopurines or MTX has been shown to contain this process[ 3]. A key step in managing IFX therapy over the more recent years is the increasing availability of therapeutic drug monitoring (TDM), that has improved response rates and has become a most effective tool for the management of secondary failure to IFX[ 37].

Increasing evidence has shown that trough IFX concentrations < 3 mg/mL during maintenance therapy are associated with treatment failure. Also, children with lower albumin levels have higher IFX clearance and lower drug exposures[ 38]. Therefore, standard IFX maintenance dosing of 5 mg/kg every 8 wk may not be adequate for all children with CD to achieve sufficient concentration level and thus minimise loss of response (Table ). Unfortunately, patients who don't respond to one anti-TNF are more likely to also fail a second agent[ 39]. Researchers hypothesized that a combination therapy of an anti-TNF antibody and another immunomodulator ( i.e., thiopurines or MTX) will increase the efficacy and reduce the risk of loss of response[ 40].

There are several adult trials showing higher treatment efficacy (especially for induction of remission) in patients receiving combination therapy. In particular, concomitant immunomodulators increase IFX levels and reduce immunogenicity[ 40]. On the other hand, combination therapy in adults exposes patients to the individual toxicity of both drugs and also seems to increase the risk of malignancy[ 40]. In paediatric IBD, the safety of combined treatment has been questioned after several cases of hepatosplenic T-cell lymphoma (HSTCL) in young patients with IBD so treated were reported.

Nevertheless, a review by Cozijnsen et al[ 40] points out that almost all studies in paediatric patients with IBD have failed to prove increased benefit from combination therapy compared to monotherapy. Given the controversial aspects above, the Authors suggest to target the use of combination therapy to children with a high risk of serious disease-related complications, such as growth delay, stricturing or fistulising CD phenotype, or panenteric CD[ 40].

In order to assess the risk of malignancies associated to immunosuppressive treatments in IBD, a retrospective multinational survey of malignancy and mortality in paediatric IBD was conducted over a 6 years period (2006-2011) by the Porto Pediatric IBD working group of ESPGHAN[ 41]. The most common malignancies identified were hematopoietic tumors ( n = 11), of which 3 were HSTCL and 3 Ebstein-Barr virus-associated lymphomas[ 41]. These 6 patients had all been treated with thiopurines until diagnosis of cancer and only 1 patient had also received 3 IFX infusions, 5 years before the diagnosis of cancer[ 41]. All 3 patients who developed HSTCL were males and had exposure to thiopurines ranging from 32 to 108 mo; none of them received a biologic[ 41].

ADA

ADA is a fully human IgG1κ monoclonal antibody which is similar to IFX in the mode of action, but it differs from it as the mouse-derived sequence is removed, in order to reduce the immunogenic reactions induced by chimeric antibodies[ 23, 34]. ADA is therefore to consider as an alternative treatment option in patients who have lost response or are intolerant to IFX, or in some primary non-responders to IFX[ 34].

ADA was recently approved in Europe and the United States for the treatment of paediatric patients with CD, based on the results from the IMAgINE-1 study[ 7, 42, 43].

IMAgINE-1 study is a phase-3, randomized, double-blind study conducted by Sharma et al[ 7] aimed to analyse the PK of ADA in a paediatric CD population ( n = 192), and to evaluate the effect of various factors, including demographics (body weight, sex), laboratory measurements (CRP, albumin), previous IFX use, concomitant immunomodulators, and baseline PCDAI, on ADA PK in paediatric patients with moderate-to-severe CD (Table ). Furthermore, the relationship between serum ADA concentration and remission/response was explored[ 24].

Trough serum ADA (measured at 5 time points from baseline up to 52 wk) and serial anti-ADA antibody measurements were performed. The study confirmed a strong positive association between serum ADA concentration and clinical remission/response to treatment[ 24]. Higher body weight, baseline CRP, and lower baseline albumin levels were associated with greater clearance of ADA (lower trough levels)[ 7]. Previous treatment with other anti-TNF therapy, presence of antibodies to previous IFX therapy, and absence of concomitant use of immunomodulators were also associated with increased clearance of ADA[ 7]. According to the published experiences from tertiary centres, in anti-TNF antibody naiive children the 1 year remission rate for ADA is 45%[ 42], and its efficacy has been documented in nearly two-thirds of patients who failed IFX[ 33]. A retrospective study was conducted by Fumery et al[ 33] who used the population-based EPIMAD registry to evaluate the effectiveness and safety of ADA in children with CD experiencing IFX failure (Table ).

Twenty-seven children with CD who received ADA before 18 years because of IFX failure or intolerance were included. Clinical response measured by the physician global assessment score after a median follow-up of 16 (8-26) mo was observed in 19 patients (70%). Cumulative probability of failure to ADA treatment at 6 mo and 1 year was 38% and 55%, respectively. Overall, the results from this population-based cohort of paediatric-onset CD with IFX failure show that treatment with ADA was safe and effective in two-thirds of patients. More specifically, ADA was effective in 100% of children intolerant to IFX, 68% of children with secondary failure to IFX, and only 25% of children with primary failure to IFX[ 33]. A systematic review on the same topic was performed by Dziechciarz et al[ 34]. Who assessed the published evidence on the efficacy and safety of ADA for CD in children (Table ).

Randomised controlled trials and observational studies (cohort studies, case series of more than 5 patients) were included. A total of 14 studies (1 randomised controlled trial, 13 case series), altogether including 664 patients (age range 1.9-21 years) were available for analysis. The pooled remission rates were: 30% at 4 wk, 42% at 6 mo and 44% at 12 mo. Of the total patients, 6% were primary non-responders and 12% had severe adverse events reported. However, studies differed with respect to patients' characteristics, including percentage of IFX-naïve patients, disease duration, disease localisation, ADA doses, treatment duration, and follow-up period[ 34].

The Authors' conclusion, though limited by the low-quality evidence based mainly on case series, is that approximately half of the children with CD on ADA therapy achieve remission during the first year of treatment with reasonable safety profile[ 34].

Vedolizumab

Vedolizumab is a recent biologic treatment, approved for adult patients with IBD in 2014. It is an anti-integrin therapy that blocks the a4b7 integrin receptor molecule present on the surface of lymphocytes, and thus inhibits the migration of intestinal T-lymphocytes into the tissue[ 39, 44, 45]. As this mechanism of action is restricted to the gastrointestinal tract, the risk of systemic immunosuppression ( i.e., infections and malignancies) seen with other IBD therapies is mitigated[ 39].

Its predecessor, natalizumab, acts with a non-specific binding to the a4 chain which causes interference with the lymphocyte trafficking in the central nervous system and led to the concern for reactivation of John Cunningham (JC) virus and subsequent development of progressive multifocal leukoencephalopathy (PML)[ 45]. Vedolizumab, being gut specific, does not interfere with immune surveillance in the central nervous system, therefore there is no risk of PML as assessed by the placebo-controlled GEMINI studies[ 44]. Anti-adhesion therapy appears to have a favourable safety profile, though the experience in children is still extremely limited[ 17]. Due to its mechanism of action of targeting gut-specific T-cell interactions, it is thought that Vedolizumab may not sufficiently treat the extra-intestinal manifestations of IBD. A dual therapy with therapeutic doses of immune-suppressants may therefore be needed to treat extra-intestinal manifestations[ 39]. So far, Vedolizumab has been particularly effective amongst UC patients, with a clinical response rate of 50% during induction[ 39]. Whilst the use of Vedolizumab has been approved for the treatment of CD and UC in adults, there is increasing off-label use in paediatric IBD[ 44].

Singh et al[ 44] conducted a retrospective review to describe the experience with Vedolizumab in 52 children with IBD (58% CD and 42% UC) at 3 tertiary IBD centres and to examine predictors of remission. Ninety percent of the patients had failed at least one anti-TNF agent. Week 14 remission rates for UC and CD were 76% and 42%, respectively ( P < 0.05). At week 4, eighty percent of anti-TNF-naive patients were in remission. At week 22, anti-TNF-naive patients had higher remission rates than those previously exposed to anti-TNF (100% vs 45%, P = 0.04). There were no safety concerns.

These results support Vedolizumab as an effective and safe treatment in children with IBD, with UC patients experiencing earlier and higher rates of remission than children with CD. Also, the data reviewed shows that anti-TNF-naive patients had higher remission rates compared to those with previous anti-TNF exposure[ 44].

Conrad et al[ 39] conducted an observational single-centre prospective cohort study aimed to determine the impact of Vedolizumab on clinical response and on achieving steroid-free remission over 22 wk of therapy. They recruited 21 children with refractory IBD (16 with CD), who had previously failed anti-TNF therapy.

Clinical response was observed in 31.6% and in 57.9% by week 6 and by week 22, respectively. Steroid-free remission was seen in 1 patient at week 6 and in 4 (20%) at week 22. No infusion reactions were observed. Vedolizumab was discontinued in 2 patients because of severe colitis, requiring surgical intervention[ 39]. These results, though limited by the small sample size, describe a number of children with severe disease who achieve clinical response in the first 6 wk and a further increase in remission rate by week 22[ 39]. Overall, the data currently available on Vedolizumab from adult and paediatric studies suggests its use as an option to achieve clinical improvement in the most severe paediatric IBD patients (both CD and UC).

Biosimilars

Biosimilars are defined as biological agents that are highly similar to another reference drug already authorized for use[ 37, 46]. This definition also implies that the quality, safety and efficacy of the biosimilar should not be affected by any molecular and/or structural dissimilarities or any potential differences in the underlying mechanisms[ 37].

Despite keeping the same aminoacid sequence as their reference drug, biosimilars end up being a different final product due to manufacturing process (including cell line, growth condition and purification processes), storage and transport, and subsequent various post-translational modiﬁcations ( e.g., glycosylation, phosphorylation, sulfation)[ 37]. Therefore, some uncertainty still exists regarding the exact drug efficacy, immunogenicity and pharmacology of biosimilars in IBD.

In 2013, the EMA authorized two IFX biosimilars, based on two randomized trials on CT-P13 (clinical development name for the biosimilar of Remicade): Remsima (Celltrion Inc., Incheon, South Korea) and Inflectra (Celltrion Inc., Hospira UK Ltd). Because both trials showed equivalent efficacy, tolerance and safety, EMA extended the approval to all indications for which the reference product is labelled, including both adult and paediatric CD and UC[ 37, 46]. At present, a number of IFX biosimilars are licensed for treatment of CD and UC also in the paediatric population.Cost containment remains one of the predominant reasons for development of biosimilars, with a reduction in costs of anti-TNF therapy for IBD by up to 70%[ 37].

Sieczkowska et al[ 46] conducted a prospective study on 32 children diagnosed with CD and 7 children with UC at 3 academic hospitals in Poland; these patients were switched from IFX originator to its biosimilar (Remsima) (Table ). Analysis of biosimilar efficacy revealed rates of clinical remission of 88 and 57% for CD and UC patients, respectively, so, in conclusion, switching from IFX originator to its biosimilar was a safe option in this cohort and after the switch, the biosimilar was just as effective as the originator[ 46].

To date, preliminary results on CT-P13 in IBD are only available from small post-marketing registries and case series with a relatively short-term follow-up period. Although this data suggests comparable efficacy and safety to IFX, more robust post-marketing studies and pharmacovigilance are warranted to evaluate the bioequivalence of CT-P13 in the coming years[ 37]. In Europe, at present, in order to switch patients with IBD from IFX originator to its biosimilar, the supervision of the treating physician and the patient's consent are both required[ 46].

THALIDOMIDE

After its suspension due to major teratogenic effects, thalidomide has been more recently re-introduced under FDA approval as an effective treatment for multiple myeloma and severe erythema nodosum leprosum. It is also extensively used off-label for immune-mediated and neoplastic conditions like discoid lupus erythematosus, erythema nodosum leprosum, Behcet's syndrome, aphthous stomatitis, juvenile idiopathic arthritis, brain tumors, graft- vs-host disease and IBD[ 5, 18, 48].

Thalidomide is used infrequently in the management of paediatric CD, nevertheless it represents a helpful option in treating children who lose response to one or more conventional agents such as thiopurines, MTX, and anti-TNF[ 48].

Thalidomide (administered from 50 to 400 mg/d in adults and 1.5 to 2.5 mg/kg per day in children[ 47]) has been shown to induce clinical remission and possibly MH[ 48]. A systematic review by Yang et al[ 5] selected twelve studies (2 RCTs and 10 case series) where thalidomide was used to induce remission in 248 patients with IBD of all age groups (10 with UC, 238 with CD), 92 of whom were children. Remission rate was 49% and 25%, in adult luminal and perianal CD respectively. In adults with UC, 50% achieved remission and 10% had a partial response. One case series reported 21 patients (17 CD, 4 UC) who maintained remission for 6 mo[ 5]. Amongst the adverse effects associated with thalidomide and reported in this review, the most common was sedation, in 32.3% of all patients, followed by peripheral neuropathy in 19.8% which was also the main cause of discontinuation[ 5]. Amongst the studies in this review, one high quality RCT showed that thalidomide is effective in inducing remission in paediatric CD[ 49]. Based on the evidence reviewed and given the limited data available, the Authors support the use of Thalidomide in the most severe cases of IBD for induction or maintenance of remission[ 5].

Lazzerini et al[ 49, 50] conducted randomized placebo-controlled trials of thalidomide in both paediatric CD and UC (Table ). In their CD trial, they randomized 52 children to receive thalidomide or placebo; almost all patients had not responded to thiopurines, and about 35% had also not responded to biologics. The majority of children had luminal disease and few had perianal disease. Although no significant response was noted at 4 wk, by 8 wk 46% of children treated with thalidomide had a reduction in their PCDAI greater than 75%, compared with 12% amongst patients treated with placebo[ 49].

Their UC trial enrolled 26 children with active UC who were randomized to receive thalidomide or placebo. All patients had active disease despite thiopurines, and about 35% had received previous IFX treatment. The UC children treated with thalidomide achieved higher remission rates at 8 wk (83% vs 19% for placebo) than those in the CD trial[ 50].

Both trials showed that thalidomide does not work quickly, as there were no significant differences between placebo and thalidomide at 4 wk, whereas major differences were seen by 8 wk[ 49, 50]. These trials also support the use of Thalidomide as a maintenance agent in cases of refractory CD or UC, for example patients with secondary loss of response to biologics[ 49, 50]. Another more recent systematic review conducted by Bramuzzo et al[ 47] analysed 722 papers, including two randomized controlled trials and 29 uncontrolled studies for a total of 489 patients, 135 (28.4%) of whom were children.

Overall, thalidomide appeared to be a promising therapy for IBD: induction of clinical remission was achieved in 51.4% of cases, and in 69.3% a clinical response was observed in the first months of treatment. In almost 50% of the cases in which endoscopy was performed, complete MH was observed and a further 15% of patients showed an improvement in their endoscopy score[ 47]. IBD remission was maintained in 72.2% after 12 mo and in 54.5% after 2 years[ 47].

Adverse events leading to drug suspension had a cumulative incidence of 19.7/1000 patients-month, with neurological symptoms being the main cause[ 48]. This review highlights that thalidomide is an effective alternative in patients who fail biologic treatment, which is most likely due to the different mechanism of action of Thalidomide compared to anti-TNF agents[ 47]. Careful precautions must be taken to avoid its use in pregnant women. No case of teratogenicity has been observed in 124000 patients enrolled in the thalidomide distribution risk management program for more than 6 years[ 49, 50]. Other reported side effects of thalidomide include peripheral neuropathy (clinical or subclinical, primarily with axonal damage) followed by sedation, constipation, mood disturbances, skin rash, pedal oedema, neutropenia and deep vein thrombosis[ 5, 48].

STUDIES ON NEW TREATMENTS

New biologics and other agents are being tested in phase II and III trials on adult patients with IBD and are therefore on the horizon within the field of paediatric gastroenterology as well. Examples are the IL-23 inhibitor risankizumab and the IL 12- IL 23 inhibitor ustekinumab. Drug therapies that interfere selectively with lymphocyte trafficking are also emerging treatment options for UC[ 11, 51]. Etrolizumab is a humanized monoclonal antibody against the b7 integrin subunit that acts by reducing the homing of leukocytes to the gut mucosa and the retention of lymphocytes in the epithelium[ 11]. It has recently been tested in a phase 2 study showing efficacy in patients with moderate to severe UC, compared to placebo[ 11]. Levels of granzyme A (GZMA) and integrin aE (ITGAE) mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab[ 11] (Table ).

Sandborn et al[ 51] performed a double-blind, placebo-controlled phase 2 trial of Ozanimod in 197 adults with moderate-to-severe UC. Clinical remission at 8 wk was observed in 16% of the patients who received 1 mg of Ozanimod and in 14% of those who received 0.5 mg, as compared with 6% of those who received placebo ( P = 0.048, P = 0.14, respectively) (Table ).

At week 32, the rate of clinical remission was 21% in the group that received 1 mg of Ozanimod, 26% in the group that received 0.5 mg of Ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively[ 51].

At week 8, absolute lymphocyte counts dropped by 49% from baseline in the group that received 1 mg of Ozanimod and by 32% from baseline in the group that received 0.5 mg[ 51]. The most common adverse events overall were anemia and headache[ 52].

From this preliminary trial, the Authors conclude that Ozanimod at a daily dose of 1 mg is more effective than placebo in inducing clinical remission of UC. However, complete assessment of clinical efficacy and safety could not be achieved by this trial due to limitations in size and duration[ 51]. Another monoclonal antibody recently investigated is the anti-natural killer group 2 member D (NKG2D), which acts by antagonising the human immunoglobulin G4 that binds to NKG2D receptors.

Change in CDAI from baseline to week 4 was the primary end-point, and was not found to differ significantly between anti-NKG2D and placebo; however, a significant difference was observed by week 12 ( P ≤ 0.10)[ 52]. The group of patients who hadn't previously failed biologics and were treated with anti-NKG2D ( n = 28) showed the most significant improvement from week 1 onward. Most adverse events were mild (49%) or moderate (43%). No antidrug antibodies were detected[ 52].

Based on the results of this trials, the Authors conclude that a single s.c. dose of 2 mg/kg anti-NKG2D did not reduce disease activity at week 4, but it showed significant response rate at week 12. Therefore, there is evidence to consider further investment in anti-NKG2D in IBD[ 52].

DISCUSSION

Though major progress has been achieved in treating IBD patients of all ages, there are still significant limitations in what is currently available to manage this condition. The advent of new biologics and other medications targeting pathways previously unexplored ( e.g., leukocyte trafficking through the gut mucosa) has provided clinicians with more hope for patients who fail to respond to current treatments. Nevertheless, whilst the causative mechanisms underlying IBD are not yet fully understood, treatment options can only target downstream components of this inflammatory chain.

IBD, and CD in particular, are difficult to categorise as distinct disease entities, as the spectrum of its clinical phenotype is very broad and variable, with mild disease responding to standard treatments, and severe disease often developing to structuring or penetrating phenotypes that require surgery, despite the use of multiple treatment escalations[ 53]. Once significant chronic bowel damage occurs in IBD, the chances of recovery with medical treatments alone are limited. Therefore, the ideal treatment should be offered before complications develop[ 53]. Step-up and top-down approaches have been debated for different risk groups of children with IBD. The management of paediatric IBD has evolved significantly over recent years with evidence-based guidelines in place to provide uniform and solid guidance in clinical practice. Nevertheless, a long-term response is only observed in less than half of the patients with CD[ 3, 52]. Although new biologics are continuously being developed, primarily monoclonal antibodies targeting the trafficking of immune cells, we certainly are in need of more therapies with novel mechanisms of action[ 52]. More significant advances have been achieved in monitoring drug administration and the response to medications, in particular the clinical availability of AZA metabolites, IFX and ADA trough levels and anti-IFX antibody measurements in clinical practice ( i.e., TDM). This has allowed a major step forward in monitoring and targeting patients' treatments with a more personalised approach.

Despite routine use of solid clinical scores ( e.g., PCDAI, PUCAI) and biochemical parameters (blood-based and stool-based), we are currently still depending on invasive reassessments ( i.e., endoscopic procedures) for an adequate monitoring of the disease course. One next goal on the horizon is therefore the development of reliable biomarkers to be used for prediction of prognostic outcomes in IBD. The ability to stratify individual patients' risk would allow clinicians to personalise treatment from disease presentation, tailoring more potent drugs (possibly in combination) to patients with a high risk of severe disease, using more standard options for patients who are destined for a milder disease course[ 53]. This individualised approach requires reliable prognostic biomarkers and hence major efforts are being made in the development of such markers. Risk stratification models would allow clinicians to treat patients effectively before complications arise, and to optimise majorly the management of patients with IBD as improve the cost effectiveness of their care[ 53].

CONCLUSION

Our narrative review summarises some of the recent advances in treating children with IBD (Table ). Whilst the mechanisms underlying this condition are yet to be fully understood, both old and new generation treatments can still only target known pathways of what is a very complex pathogenesis. A significant proportion of children with IBD does not respond to currently available treatments, either at diagnosis or during disease course, therefore new treatment options are urgently needed. Major advances have been achieved in monitoring the individual metabolism, toxicity and response to treatments in IBD. Amongst the priorities in current research is the development of reliable prognostic biomarkers, an essential step towards the personalised treatment of patients with IBD.

Table 2

1. The pathogenesis of IBD is not completely understood yet, and all therapies currently available are aimed at downstream steps of the complex inflammatory process. Specific targets when treating children with IBD are achieving satisfactory growth and nutritional status.

2. Paediatric pharmacometric approaches are increasingly applied to drugs already in use but that remain unlicensed and off-label in children due to missing information on age appropriate dosing, efficacy and safety.

3. Corticosteroids can be used to induce remission in CD (when exclusive enteral nutrition is not possible) and are first-line therapy for induction of remission in UC, particularly in case of non-response to 5-ASA or with severe presentation.

4. One of the targets of current research is to customise therapy to a patient's predictive biomarker profile in order to personalise treatments and to maximise response.

5. 5-ASA are used in induction and maintenance of remission in UC. They are not recommended in CD except from post-operative maintenance of remission.

6. Thiopurines include AZA and 6-MP and are steroid sparing agents. They are effective in maintaining disease remission in patients with CD and UC as well as post-surgical remission in CD. The use of TPMT activity and 6-TGN level measurements helps avoiding nearly a quarter of episodes of myelosuppression as well as to monitor non-compliance, under-dosing, drug-resistance or refractory state.

7. An increase in mean 6-TGN blood level has been reported in patients on 6-MP or AZA co-treated with 5-ASA, with a higher rate of myelotoxicity in respect to patients treated with the thiopurine alone.

8. MTX is effective in 50%-80% of the children who fail to respond or are intolerant to thiopurines. It is particularly suitable to patients who have coexistent inflammatory arthritis.

9. In CD, anti-TNF agents are used to treat moderate to severe disease with inadequate response, or contraindication to, or intolerance to, conventional therapy including corticosteroids and immunomodulators. They are also indicated in children with active perianal fistulising disease. Therapeutic drug monitoring of IFX has improved response rates and is increasingly used in clinical practice as a tool for the management of secondary failure to IFX.

10. ADA is a fully human IgG1k monoclonal antibody, which represents a treatment option in patients who have lost response or are intolerant to IFX. ADA achieves remission rates of 45% at 1 yr in anti-TNF naïve children and is effective in nearly 2/3 of patients with IFX failure.

11. Vedolizumab is an anti-integrin therapy which inhibits the migration of intestinal T lymphocytes. The mechanism of action of Vedolizumab is restricted to the GI tract, mitigating the risks of systemic immunosuppression such as infections and malignancies. The clinical response rate for induction with vedolizumab is 50% in UC patients. Vedolizumab is approved for treatment of CD and UC in adults and there is increasing off-label use in children.

12. Thalidomide is an immunosuppressant drug used infrequently off-label in the treatment of refractory CD and UC. Induction of remission is achieved in aroud 50% cases and clinical response in 70%.

13. Drug therapies that interfere selectively with lymphocyte trafficking ( e.g., etrolizumab, ozanimod) are emerging treatment options for UC.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Italy

Peer-review report classification

Grade A (Excellent): A, A

Grade B (Very good): B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

Conflict-of-interest statement: No potential conflicts of interest. No financial support.

Peer-review started: February 28, 2017

First decision: April 7, 2017

Article in press: July 24, 2017

P- Reviewer: Matowicka-Karna J, Tambuwala M, Zhang MZ S- Editor: Qi Y L- Editor: A E- Editor: Zhang FF

References

# data[].attributes.attachment_link.title
Treating children with inflammatory bowel disease: Current and new perspectives

# data[].attributes.attachment_link.description
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gut characterised by alternating periods of remission and relapse. Whilst the mechanism underlying this disease is yet to be fully understood, old and newer generation treatments can only target selected pathways of this complex inflammatory process.

# data[].attributes.headline
Probiotic Supplementation in Celiac Patients With Persistent IBS-type Symptoms - Mitchell Watts

# data[].attributes.subject
Probiotic Supplementation in Celiac Patients With Persistent IBS-type Symptoms - Mitchell Watts

# data[].attributes.body
1) I found this study interesting and potentially important, because even if a patient has strict adherence to a gluten-free diet, IBS type symptoms can still occur. According to the authors, in another metanalysis this persistence of symptoms could be related to motor dysfunction, gut inflammation, small intestinal disease, visceral hypersensitivity, and altered gut microbiota. This altered gut microbiome can persist even if a patient follows a strict gluten free diet. This could be related to the adherence to the diet due to decreased intake of polysaccharides that serve as prebiotics for gut microbes. The objective of this study was to evaluate whether probiotic supplementation was able to improve GI symptoms, specifically using a mixture of probiotic strains that were found to be deficient per microbiological data (three bifidobacteria and two lactobacilli). This potentially important, because it could be beneficial for patients with celiac disease to not only adhere to a strict gluten-free diet, but also start probiotic supplementation as well.

2) According to the results, the intervention led to decreased severity of IBS type symptoms. They believe this effect could be due to modification of the microbiome with an increase in bifidobacteria in fecal samples. One result I found interesting is that the IBS-SSS and GSRS scores decreased significantly in the intervention, even though these values were originally higher in the intervention group compared to placebo. This additionally could support the role of probiotic supplementation. As I allude to in the clinical implications, I could imagine increasing intake of food sources of bifidobacterial and lactobacilli could result in similar findings.

3) The implications of this study could support probiotic supplementation for patients with celiac disease with persistent IBS type symptoms. Additionally, I would postulate that consuming food sources of bifidobacterial and lactobacilli, including yogurt, kefir, kimchi, and other gluten-free fermented foods would potentially be beneficial. I would also think it is important to increase intake of prebiotic foods, including gluten-free whole grains, onions, garlic, bananas, berries, etc.

Francavilla, R., Piccolo, M., Francavilla, A., Polimeno, L., Semeraro, F., Cristofori, F., Castellaneta, S., Barone, M., Indrio, F., Gobbetti, M., & De Angelis, M. (2019). Clinical and Microbiological Effect of a Multispecies Probiotic Supplementation in Celiac Patients With Persistent IBS-type Symptoms: A Randomized, Double-Blind, Placebo-controlled, Multicenter Trial. Journal of clinical gastroenterology, 53(3), e117–e125. https://doi.org/10.1097/MCG.0000000000001023

# data[].attributes.attachment_link.readable_text
Affiliations

¹ Department of Interdisciplinary Medicine.

² Department of Soil, Plant and Food Science.

³ IRCCS "Saverio De Bellis," Castellana Grotte.

⁴ Gastroenterology Unit, PO Centrale Taranto, Taranto.

⁵ Department of Pediatrics, PO San Paolo, Bari.

⁶ Department of Emergency and Organ Transplantation, University of Bari Aldo Moro.

⁷ Faculty of Science and Technology, Piazza Università, Free University of Bozen, Bolzano, Italy.

Free PMC article

Randomized Controlled Trial

Free PMC article

Affiliations

¹ Department of Interdisciplinary Medicine.

² Department of Soil, Plant and Food Science.

³ IRCCS "Saverio De Bellis," Castellana Grotte.

⁴ Gastroenterology Unit, PO Centrale Taranto, Taranto.

⁵ Department of Pediatrics, PO San Paolo, Bari.

⁶ Department of Emergency and Organ Transplantation, University of Bari Aldo Moro.

⁷ Faculty of Science and Technology, Piazza Università, Free University of Bozen, Bolzano, Italy.

Abstract

Goals: The goals of this study were to evaluate the efficacy and safety of a probiotic mixture in patients with celiac disease (CD) with irritable bowel syndrome (IBS)-type symptoms despite a strict gluten-free diet (GFD).

Background: About 30% of patients with CD adherent to a GFD suffer from IBS-type symptoms; a possible cause resides in the imbalances of the intestinal microbiota in CD. Probiotics may represent a potential treatment.

Study: CD patients with IBS-type symptoms entered a prospective, double-blind, randomized placebo-controlled study. A 6-week treatment period was preceded by a 2-week run-in and followed by a 6-week follow-up phase. Clinical data were monitored throughout the study by validated questionnaires: IBS Severity Scoring System (IBS-SSS); Gastrointestinal Symptom Rating Scale (GSRS); Bristol Stool Form Scale (BSFS); and IBS Quality of Life Questionnaire (IBS-QOL). The fecal microbiota were assayed using plate counts and 16S rRNA gene-based analysis.

Results: In total, 109 patients were randomized to probiotics (n=54) or placebo (n=55). IBS-SSS and GSRS decreased significantly in probiotics, as compared with placebo [(-15.9%±14.8% vs. 8.2%±25.9%; P<0.001) and (-19.8%±16.6% vs. 12.9%±31.6%; P<0.001)], respectively. Treatment success was significantly higher in patients receiving probiotics, as compared with placebo (15.3% vs. 3.8%; P<0.04). Presumptive lactic acid bacteria, Staphylococcus and Bifidobacterium, increased in patients receiving probiotic treatment. No adverse events were reported.

Conclusions: A 6-week probiotic treatment is effective in improving the severity of IBS-type symptoms, in CD patients on strict GFD, and is associated with a modification of gut microbiota, characterized by an increase of bifidobacteria.

References

Lebwohl B, Sanders DS, Green PHR. Lancet. Coeliac disease. 2017;S0140-6736:31796-31798. - PubMed

Sainsbury A, Sanders DS, Ford AC. Prevalence of irritable bowel syndrome-type symptoms in patients with celiac disease: a meta-analysis. Clin Gastroenterol Hepatol. 2013;11:359-365. - PubMed

Aziz I, Sanders DS. The irritable bowel syndrome-celiac disease connection. Gastrointest Endosc Clin N Am. 2012;22:623-637. - PubMed

Pagliari D, Urgesi R, Frosali S, et al. The interaction among microbiota, immunity, and genetic and dietary factors is the condicio sine qua non celiac disease can develop. J Immunol Res. 2015;2015:123653. - PMC - PubMed

Collado MC, Donat E, Ribes-Koninckx C, et al. Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. Austin J Clin Pathol. 2009;62:264-269. - PubMed

# data[].attributes.attachment_link.keywords[]
irritable bowel syndrome / diet therapy*

# data[].attributes.attachment_link.keywords[]
irritable bowel syndrome / physiopathology

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Clinical and Microbiological Effect of a Multispecies Probiotic Supplementation in Celiac Patients With Persistent IBS-type Symptoms: A Randomized, Double-Blind, Placebo-controlled, Multicenter Trial - PubMed

# data[].attributes.attachment_link.description
1 Department of Interdisciplinary Medicine. 2 Department of Soil, Plant and Food Science. 3 IRCCS "Saverio De Bellis," Castellana Grotte. 4 Gastroenterology Unit, PO Centrale Taranto, Taranto. 5 Department of Pediatrics, PO San Paolo, Bari. 6 Department of Emergency and Organ Transplantation, University of Bari Aldo Moro.

# data[].attributes.headline
Nutritional Regimes Enriched with Antioxidants as an Efficient Adjuvant for IBD Patients under Infliximab Administration, a Pilot Study

# data[].attributes.subject
Nutritional Regimes Enriched with Antioxidants as an Efficient Adjuvant for IBD Patients under Infliximab Administration, a Pilot Study

# data[].attributes.body
This study is important because it evaluates the potential impact of incorporating a nutritional supplement, more specifically antioxidants, along with an Infliximab (IFX) treatment. The treatment is geared towards both Crohn’s disease (CD) patients and Ulcerative colitis (UC) patients and blocks TNF-alpha, which is a inflammatory cytokine. In this study, when an antioxidant rich supplement (purple corn extract) was administered with the IFX treatment, it enhanced the results of the treatment in both CD and UC patients. This relates to nutritional sciences because it highlights the possibility of diet impacting the effectiveness of IBD treatments that are currently being used. As we know, IBD is different for every patient and treatment has to be very individualized. This study shifts the focus from new treatments and medications to the potential of nutritional adjuvants that can be paired with treatments that are already being used. This could potentially enhance the impact of these treatments, making it less individualized to the patient.

Liso M, Sila A, Verna G, Scarano A, Donghia R, Castellana F, Cavalcanti E, Pesole PL, Sommella EM, Lippolis A, Armentano R, Giudetti AM, Vergara D, Campiglia P, Sardone R, Curlo M, Mastronardi M, Petroni K, Tonelli C, Santino A, Chieppa M. Nutritional Regimes Enriched with Antioxidants as an Efficient Adjuvant for IBD Patients under Infliximab Administration, a Pilot Study. Antioxidants. 2022; 11(1):138. https://doi.org/10.3390/antiox11010138

# data[].attributes.headline
COVID-19 and Outcomes in Patients with Inflammatory Bowel Disease

# data[].attributes.subject
COVID-19 and Outcomes in Patients with Inflammatory Bowel Disease

# data[].attributes.body
I found an article about the clinical outcomes of COVID-19 in IBD patients. I was interested in looking into this because I had read elsewhere that a possible implication of the Covid virus was an onset of autoimmune diseases. The study is important in order to determine the impact of COVID-19 in patients with IBD.  They observed that patients with IBD are at an increased risk of COVID-19 infection, most specifically when they have active disease and are taking immunosuppressive therapy.  However, the prevalence of COVID-19 in IBD patients was low. The use of corticosteroids or mesalamine was associated with worse outcomes, whereas anti-TNFs was associated with more favorable outcomes. Since flares in active IBD patients who have COVID are increased, it relates to nutritional sciences as these patients need to be more cautious of what they intake in order not to worsen this terrible situation. Patients reported that during flare ups, avoiding foods high in fiber reduced symptoms. The clinical implications of the study was to clarify and identify risk factors and coping mechanisms for patients with IBD, who have been infected with COVID-19. Nutrition is obviously linked to immunity and infections and patients with chronic inflammatory diseases must be mindful of their nutritional status as this puts them at a greater risk of infections including COVID-19.

Tripathi, Kartikeya, et al. “COVID-19 and Outcomes in Patients with Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.” Inflammatory Bowel Diseases, 2021, https://doi.org/10.1093/ibd/izab236.

# data[].attributes.body
Sun Y, Li L, Xie R, Wang B, Jiang K
and Cao H (2019) Stress Triggers
Flare of Inflammatory Bowel Disease
in Children and Adults.
Front. Pediatr. 7:432.
doi: 10.3389/fped.2019.00432
This is a review of many different studies, but it is important because of the toll that stress can take on our bodies and immune system. Perceived chronic stress has the ability to ramp up the inflammatory process so it is very important to look at it as a mitigating factor in IBD

One key finding of a study reviewed in the paper is that stress affects IBD by disturbing the gut microbiota. They reviewed a study done based on a dextran sulfate sodium (DSS)-induced colitis mouse model. The results were that chronic stress increases sensitivity to colitis by way of dysbiosis and immune system dysfunction. This relates to nutritional sciences because, based on other studies reviewed, there are nutritional supplements like pre or probiotics which can help prevent stress-induced flare ups of types of IBD.

Clinical implications of the microbiota study reviewed in the paper is that there are therapies that can be prescribed that target the microbiome to treat IBD. Some mentioned are antibiotics, probiotics, fecal transplants that can be helpful not only physically, but for mental recovery of IBD.

# data[].attributes.headline
How changes to the American Diet affects Crohn's Disease models in mice

# data[].attributes.subject
How changes to the American Diet affects Crohn's Disease models in mice

# data[].attributes.body
Inflammatory Bowel Diseases such as Crohn’s disease have a much higher prevalence in developed countries.  It has long been understood that diet plays a role in inflammation levels of the intestines.  However, which dietary component plays the largest role was still in question. Researchers looked evaluated the three main macronutrients found in the typical American diet (AD) based on a 2011-2012 NHANES report.  These American diet macronutrients were animal protein, refined carbohydrates, and high ω-3: ω-6 fat ratios.  Each macronutrient was evaluated.  The mice that are chow with plant-based protein instead of animal protein showed significantly less intestinal inflammation and reduced weight loss.  Additionally, changes were seen in the microbiome composition of the Crohn’s mice on the plant-based protein diet as opposed to those on the animal protein.  This study supports the idea that changing from animal to plant-based protein sources could greatly improve intestinal inflammation in Crohn’s patients.  With the availability of products like Impossible, patients may see symptom improvement without making major dietary changes.

Raffner Basson, Gomez-Nguyen, A., LaSalla, A., Buttó, L., Kulpins, D., Warner, A., Di Martino, L., Ponzani, G., Osme, A., Rodriguez-Palacios, A., & Cominelli, F. (2021). Replacing Animal Protein with Soy-Pea Protein in an “American Diet” Controls Murine Crohn Disease-Like Ileitis Regardless of Firmicutes: Bacteroidetes Ratio. The Journal of Nutrition, 151(3), 579–590. https://doi.org/10.1093/jn/nxaa386

# data[].attributes.attachment_link.readable_text
Affiliations

¹ Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.

² Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

³ Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

Free PMC article

Free PMC article

Affiliations

¹ Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.

² Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

³ Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

Abstract

Background: The current nutritional composition of the "American diet" (AD; also known as Western diet) has been linked to the increasing incidence of chronic diseases, including inflammatory bowel disease (IBD), namely Crohn disease (CD).

Objectives: This study investigated which of the 3 major macronutrients (protein, fat, carbohydrates) in the AD has the greatest impact on preventing chronic inflammation in experimental IBD mouse models.

Methods: We compared 5 rodent diets designed to mirror the 2011-2012 "What We Eat in America" NHANES. Each diet had 1 macronutrient dietary source replaced. The formulated diets were AD, AD-soy-pea (animal protein replaced by soy + pea protein), AD-CHO ("refined carbohydrate" by polysaccharides), AD-fat [redistribution of the ω-6:ω-3 (n-6:n-3) PUFA ratio; ∼10:1 to 1:1], and AD-mix (all 3 "healthier" macronutrients combined). In 3 separate experiments, 8-wk-old germ-free SAMP1/YitFC mice (SAMP) colonized with human gut microbiota ("hGF-SAMP") from CD or healthy donors were fed an AD, an AD-"modified," or laboratory rodent diet for 24 wk. Two subsequent dextran sodium sulfate-colitis experiments in hGF-SAMP (12-wk-old) and specific-pathogen-free (SPF) C57BL/6 (20-wk-old) mice, and a 6-wk feeding trial in 24-wk-old SPF SAMP were performed. Intestinal inflammation, gut metagenomics, and MS profiles were assessed.

Results: The AD-soy-pea diet resulted in lower histology scores [mean ± SD (56.1% ± 20.7% reduction)] in all feeding trials and IBD mouse models than did other diets (P < 0.05). Compared with the AD, the AD-soy-pea correlated with increased abundance in Lactobacillaceae and Leuconostraceae (1.5-4.7 log2 and 3.0-5.1 log2 difference, respectively), glutamine (6.5 ± 0.8 compared with 3.9 ± 0.3 ng/μg stool, P = 0.0005) and butyric acid (4:0; 3.3 ± 0.5 compared with 2.54 ± 0.4 ng/μg stool, P = 0.006) concentrations, and decreased linoleic acid (18:2n-6; 5.4 ± 0.4 compared with 8.6 ± 0.3 ng/μL plasma, P = 0.01).

Conclusions: Replacement of animal protein in an AD by plant-based sources reduced the severity of experimental IBD in all mouse models studied, suggesting that similar, feasible adjustments to the daily human diet could help control/prevent IBD in humans.

Keywords: American diet; Firmicutes:Bacteroidetes ratio; inflammatory bowel disease; pea protein; soy protein.

Similar articles

Slaughter value and meat quality of broiler chickens fed with rations containing a different share of pea seed meal.

Janocha A, Milczarek A, Łaski K, Głuchowska J. Janocha A, et al. Acta Sci Pol Technol Aliment. 2021 Jul-Sep;20(3):265-276. doi: 10.17306/J.AFS.0914. Acta Sci Pol Technol Aliment. 2021. PMID: 34304545

Nutritional Therapies and Their Influence on the Intestinal Microbiome in Pediatric Inflammatory Bowel Disease.

Hart L, Verburgt CM, Wine E, Zachos M, Poppen A, Chavannes M, Van Limbergen J, Pai N. Hart L, et al. Nutrients. 2021 Dec 21;14(1):4. doi: 10.3390/nu14010004. Nutrients. 2021. PMID: 35010879 Free PMC article. Review.

Regulation of Intestinal Inflammation by Soybean and Soy-Derived Compounds.

Basson AR, Ahmed S, Almutairi R, Seo B, Cominelli F. Basson AR, et al. Foods. 2021 Apr 4;10(4):774. doi: 10.3390/foods10040774. Foods. 2021. PMID: 33916612 Free PMC article. Review.

Food and Food Groups in Inflammatory Bowel Disease (IBD): The Design of the Groningen Anti-Inflammatory Diet (GrAID).

Campmans-Kuijpers MJE, Dijkstra G. Campmans-Kuijpers MJE, et al. Nutrients. 2021 Mar 25;13(4):1067. doi: 10.3390/nu13041067. Nutrients. 2021. PMID: 33806061 Free PMC article. Review.

# data[].attributes.attachment_link.keywords[]
dietary proteins / administration & dosage*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Replacing Animal Protein with Soy-Pea Protein in an "American Diet" Controls Murine Crohn Disease-Like Ileitis Regardless of Firmicutes: Bacteroidetes Ratio - PubMed

# data[].attributes.attachment_link.description
1 Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH, USA. 2 Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. 3 Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

# data[].attributes.headline
Dietary patterns, beliefs and behaviors among individuals with inflammatory bowel disease: a cross-sectional study.

# data[].attributes.subject
Dietary patterns, beliefs and behaviors among individuals with inflammatory bowel disease: a cross-sectional study.

# data[].attributes.body
https://doi.org/10.1111/jhn.12786

1)This study is important because it evaluated the beliefs of patients and what they thought worked, versus using recommendations from health professionals to decide for the patients what works. Seems to give more actual patient results, which could be helpful for other IBD patients to read and make changes from. Specifically, the study found that, “Eighty-three percent believed that modifying their diet could reduce IBD symptoms.” Regarding nutrition suggestions, there can be patient resistance when there are large lifestyle changes discussed with healthcare providers, not always but it can definitely happen. This is likely because making big changes, especially with what you eat, can be intimidating and feel really difficult. Additionally, you cannot guarantee you will be satisfied, or see the symptoms improvement, etc. So, when you can hear more personal stories or results from fellow patients it can lead to changes being made which can impact your health and wellbeing.

2)One key finding from this study was, “Both men and women with IBD struggle to meet the national guidelines for intake of fiber, whole grains, fruits and vegetables. The majority reported modifying their dietary intake as a result of IBD and expressed belief that diet could reduce symptoms.” This relates to nutritional sciences because it broke down each of the requirements for dietary intake, like calcium, fruits, dairy, etc., and evaluated the intake amongst participants with the diet modifications they made to show where they found some relief of symptoms later from making changes.

3) The clinical implications of this study were support for national guidelines of dietary intake recommendations that if followed showed relief of symptoms for IBD patients. Dietary modifications have been identified as a difficult topic and process for patients, but once done have provided more overall relief. IBD is not a disease that can be cured but can be managed through medications and lifestyle modifications. This study works to highlight the impact nutrition can make on a disease symptomology and patient wellness.

Kamp, K.J, and B Pennings. “Dietary Patterns, Beliefs and Behaviors among Individuals with Inflammatory Bowel Disease: a Cross-Sectional Study.” Wiley Online Library, 14 June 2020, https://doi.org/10.1111/jhn.12786.

# data[].attributes.body
The study I selected for this module talks about how important a nutrition education program that is carried out by a registered dietician could improve the nutritional status of pediatric patients with celiac disease. This program will focus on having a balanced GFD and improving the physical activity levels of patients to further ensure an improved quality of diet. This is important because it could be difficult for celiac disease patients to adjust to a new diet and this program can enable them maintain a healthy lifestyle. One finding from the study was that after patients participated in the nutrition intervention program, their diet changed from just being rich in fats and protein and deficient in carbohydrate to eating foods that are mainly plant based and a decreased amount of meat, diary and processed food in their diets. These results show the role nutritional sciences can play in helping patients with celiac disease adjust to their new diets and ensure they are still getting all the form of nutrition they need. The clinical implication of this study is ensuring that in the treatment plans of children with celiac disease, a nutritional education should be part of the treatment to bring about healthy eating habits and improve the quality of the children’s diet.
Citation
Suárez‐González, M., Bousoño García, C., Jiménez Treviño, S., Iglesias Cabo, T., & Díaz Martín, J. J. (2020). Influence of Nutrition Education in Paediatric coeliac disease: Impact of the role of the registered dietitian: A prospective, single‐arm intervention study. Journal of Human Nutrition and Dietetics, 33(6), 775–785. https://doi.org/10.1111/jhn.12800.

# data[].attributes.headline
A randomized phase I study of etrolizumab in moderate to severe ulcerative colitis 

# data[].attributes.subject
A randomized phase I study of etrolizumab in moderate to severe ulcerative colitis 

# data[].attributes.body
This study is important because it will help discover new ways to help reduce problems regarding moderate to severe ulcerative colitis. Etrolizumab is supposed to inhibit the migration of lymphocytes to the gut. Lymphocytes to the gut is the main cause for inflammations in inflammatory bowel disease and using selective antimigration therapies are aimed to protect the gut. A finding of this study says how effective this pharmacological drug is compared to changing a persons diet as a whole. Clinical implications state that a therapy developed to block migration of harmful cells to the gut and instead recruiting effective cells it would become an effective/ more improved therapy. While migration blockers are considered tolerable, there still needs to be further research done to truly understand its impact.

Citation:
Rutgeerts, Fedorak, R. N., Hommes, D. W., Sturm, A., Baumgart, D. C., Bressler, B., Schreiber, S., Mansfield, J. C., Williams, M., Tang, M., Visich, J., Wei, X., Keir, M., Luca, D., Danilenko, D., Egen, J., & O’Byrne, S. (2013). A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis. Gut, 62(8), 1122–1130. https://doi.org/10.1136/gutjnl-2011-301769

# data[].attributes.attachment_link.readable_text
Log in using your linkblue account, but do use the "AD\" or "MC\" prefix, and do NOT use the "@uky.edu" suffix.

To access restricted UK Library resources while off-campus you must log in using your linkblue account--the same as for MyUK and other UK Internet services. Please see EZProxy instructions for more information, or send questions about this service to the Library's webadmin@lsv.uky.edu list.

Electronic resources are licensed for the noncommercial, educational, and research use of University of Kentucky students and employees and those who are physically present at our library facilities.

Systematic downloads, distribution or long-term storage of substantial portions of information is prohibited. By using these products you are agreeing to the terms and conditions for the use of electronic resources .

This page was last updated 10/5/2021.

# data[].attributes.attachment_link.description
Log in using your linkblue account, but do use the "AD\" or "MC\" prefix, and do NOT use the "@uky.edu" suffix. To access restricted UK Library resources while off-campus you must log in using your linkblue account--the same as for MyUK and other UK Internet services.

# data[].attributes.headline
Gluten-Free Diet: How Strict Should It Be?

# data[].attributes.subject
Gluten-Free Diet: How Strict Should It Be?

# data[].attributes.body
The article for this week evaluates the safe threshold of ingestion of contaminating gluten for patients with celiac disease. Current guidelines suggest a life long gluten free diet with patients with celiac disease. This has been shown to restore the mucosal abnormalities resulting from an autoimmune reaction to patients that ingest gliadin(gluten). But can research confirm that these diet's were 100% gluten free? There is evidence that many gluten free products actually contain gluten from either contamination or because it's allowed by the FDA to be categorized as “gluten-free” if it contains less than 20ppm. Several studies have established a safe threshold of daily gluten intake. One study found that patients who had received 100 mg gliadin/day (= about 200 mg of gluten) displayed minimal morphometric changes in the histology of the small intestine. Changes were not significant until a dose of 500mg gliadin/day. This is important because the hardship on celiac patients to stay gluten-free can end up in relapse of symptoms and strain their mental health. Clinical implications include case-by-case diagnosing and treatment plans for celiac patients. Some patients will be able to tolerate daily intake of gluten without an immune response.

Itzlinger, A., Branchi, F., Elli, L., & Schumann, M. (2018). Gluten-Free Diet in Celiac Disease-Forever and for All?. Nutrients, 10(11), 1796. https://doi.org/10.3390/nu10111796

# data[].attributes.headline
Anxiety and depression in adult patients with celiac disease on a gluten-free diet

# data[].attributes.subject
Anxiety and depression in adult patients with celiac disease on a gluten-free diet

# data[].attributes.body
The article I will be discussing for this week looked further into individuals who have celiac disease and it’s correlation with anxiety and depression within the adult population. I was interested in looking deeper into this because one of my family members was recently diagnosed with celiac disease not by her physical symptoms; but by her high levels of anxiety and panic attacks she was experiencing. She has mentioned that those feelings of anxiety and panic attacks have subsided drastically since she has started a gluten free diet. This is important to note because there could be symptoms of these diseases that aren’t just physical for some patients, but also psychological. This also could be important if simply changing one’s diet could impact their mental health.

The study looked at individuals diagnosed with celiac disease, inflammatory bowel disease in remission or slight disease activity, and a general population group (used as their control group). To assess depression and anxiety within these groups they used the Hospital Anxiety and Depression Scale, this assessment focuses on individuals who have anxiety or depression but also takes into account the individual has a physical illness as well. Overall the study found that the individuals diagnosed with both celiac disease and inflammatory bowel disease had a higher rate of anxiety compared to the general population group. The celiac group had a higher rate of anxiety compared to the inflammatory bowel disease patients.

This raises a few questions for me, should treatment for celiac be different in patients who have anxiety or depression? How does treatment for anxiety and depression differ in celiac patients, are they less effective due to decreased absorption?

# data[].attributes.attachment_link.title
Anxiety and depression in adult patients with celiac disease on a gluten-free diet

# data[].attributes.attachment_link.description
AIM: To compare anxiety and depression levels in adult patients with celiac disease (CD) on a gluten-free diet (GFD) with controls.METHODS: The levels of anxiety, depression and of a probable anxiety or depressive disorder were assessed by the Hospital ...

# data[].attributes.body
I found an article about the risk of colorectal cancer for inflammatory bowel disease patients. This article is important because IBD patients have an increased risk in developing colorectal cancer, due to the increase of colitis. Colorectal cancers are caused by longer durations of colitis, which is the inflammation of the colon. This occurs frequently in patients with IBD. Due to cancer being a risk for these patients, biopsies are needed to monitor the presence of disease in IBD patients. It has also been found that IBD patients that also have been diagnosed with Cronh's disease are at an even higher risk for these cancers. A key finding found in this article, was that chronic IBD patients typically have a folate deficiency. This is due to lack of folate in their nutritional intake. Colorectal cancers are associated with low folate intake. It was determined that folate supplementation for IBD patients can decrease the risk of these cancers. The clinical implications from this study are that patients with IBD should be tested for cancers to monitor the increased risk of colorectal cancers through rectal biopsies and stool samples. IBD patients can also talk with their primary care physicians to talk about nutritional supplementation, such as folate supplements, to reduce the risk of developing these cancers.

Xie, J., & Itzkowitz, S. H. (2008). Cancer in inflammatory bowel disease. World journal of gastroenterology, 14(3), 378–389. https://doi.org/10.3748/wjg.14.378

# data[].attributes.attachment_link.readable_text
Abstract

Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Colon cancer risk in inflammatory bowel disease increases with longer duration of colitis, greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. Chemoprevention includes aminosalicylates, ursodeoxycholic acid, and possibly folic acid and statins. To reduce CRC mortality in IBD, colonoscopic surveillance with random biopsies remains the major way to detect early mucosal dysplasia. When dysplasia is confirmed, proctocolectomy is considered for these patients. Patients with small intestinal Crohn's disease are at increased risk of small bowel adenocarcinoma. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal-anastomosis have a rather low risk of dysplasia in the ileal pouch, but the anal transition zone should be monitored periodically. Other extra intestinal cancers, such as hepatobiliary and hematopoietic cancer, have shown variable incidence rates. New endoscopic and molecular screening approaches may further refine our current surveillance guidelines and our understanding of the natural history of dysplasia.

Keywords: Colon cancer, Inflammatory bowel disease, Dysplasia, Chemoprevention, Colonoscopy, Genomic instability

INTRODUCTION

The two forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic, relapsing inflammation of the intestines. First described in a report by Crohn and Rosenberg in 1925[ 1], colorectal cancer (CRC) in patients with IBD has long been recognized. Even years after their disease is controlled with medications, IBD patients still live with the fear of developing cancer. CRC is the most common site of cancer in IBD, although cancer in other organs can occur. Together with the hereditary syndromes of familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, IBD is among the top three high-risk conditions for CRC. To date, our understanding of CRC pathobiology has come from studies of patients with UC more so than Crohn's colitis. This review will focus mainly on the problem of CRC, and then address other cancers such as small intestinal adenocarcinoma, cholangiocarcinoma, and hematologic malignancies.

COLORECTAL CANCER IN PATIENTS WITH IBD

Prevalence and Incidence of CRC

The exact magnitude of the risk of cancer has been difficult to quantify due to various biases and methodological errors in published studies. Early estimates of CRC complicating UC were based on crude percentages and all were from major medical institutions, predominantly tertiary referral centers. Studies from these centers often included a greater proportion of patients who had more severe disease and cancer had already complicated their colitis. These center-based studies often overestimate the risk. Later population-based studies tended to include more patients with limited disease or those who have undergone colectomy and may thereby underestimate the true risk. Based on a 2001 meta-analysis by Eaden et al, including 116 studies from around the world, the prevalence of CRC in patients with UC is approximately 3.7% overall and 5.4% for those with pancolitis[ 2]. In comparison, CRC in Crohn's disease has been less well studied. Early studies showed no statistically significant increase in cancer risk among the Crohn's disease patients. However, the lack of the risk of cancer in these studies was often due to inclusion of all patients with Crohn's disease and failed to correct for the small subsets of those with extensive, longstanding and unresected colonic disease. Hence, when patients with longstanding, anatomically substantial Crohn's colitis are considered, the risk of CRC is similar between Crohn's colitis and UC[ 3]. Indeed, a population-based study from Manitoba, Canada found that the risk for colon cancer among patients with both UC and Crohn's colitis is approximately 2-3 fold greater than the general population and that the risk of rectal cancer is increased 2-fold in UC but not Crohn's colitis[ 4].

Clinical features of colitis-associated CRC

Compared with sporadic colorectal carcinoma (SCC), CRC arising in patients with IBD has several distinguishing clinical features. Colitis-associated colorectal cancer (CAC) affects individuals at a younger age than the general population. CAC progresses to invasive adenocarcinoma from flat and nonpolypoid dysplasia more frequently than SCC. CACs more often have a higher proportion of mucinous and signet ring cell histology. There is background of chronic inflammation in colitis and a higher rate of two or more synchronous primary CRCs. The multifocality of CAC relates to the broader field effect of mucosal inflammation that gives rise to the neoplasia. In some studies, patients were found to have cancer more proximal in the colon. Finally, the sequence of molecular events leading from dysplasia to invasive adenocarcinoma is different from that of SCC (discussed below).

Molecular features of sporadic colon cancer

To place the molecular pathogenesis of colitis-associated neoplasia in proper perspective, it is important to appreciate the molecular events involved in the development of SCC. SCC arises as a result of genomic instability. The two main types of genomic instability that contribute to colon carcinogenesis are chromosomal instability (CIN) and microsatellite instability (MSI), accounting for 85% and 15% of SCC, respectively. Chromosomal instability results in abnormal segregation of chromosomes and abnormal DNA content (aneuploidy). As a result, loss of chromosomal material (loss of heterozygosity) often occurs, such as APC and p53. These genes can also be rendered nonfunctional by mutation.

Loss of APC function is typically an early event in SCC pathogenesis. The APC gene thus has been considered the "gatekeeper" of the colon (Figure ). Some 85% of all sporadic and inherited colorectal tumors show loss of APC function, usually through protein truncation or allelic loss[ 5]. The APC gene is located on chromosome 5q21-q22. The key tumor suppressor function of the APC protein lies in its ability to destabilize free β-catenin[ 6]. Among the 15% of colon carcinomas that retain wild-type APC, point mutations have been found in β-catenin that change one of the four serine/threonine residues in the N-terminus, the putative targets of glycogen synthase kinase-3β (GSK-3β)[ 7]. These mutations thus render β-catenin refractory to phosphorylation by GSK-3β, increasing free β-catenin levels. Accumulation of stabilized free β-catenin is an early event and perhaps the initiating event in intestinal tumorigenesis. Inactivation of both APC alleles is found in a majority of small colorectal adenomas in humans and in the smallest detectable tumors in mice heterozygous for an inactivating mutation in APC[ 8]. Furthermore, intestine-specific expression of a dominant-negative form of β-catenin, which lacks the putative GSK-3β targets sites, leads to the development of adenomas[ 9]. How the loss of APC or stabilization of β-catenin leads to development of cancer is not yet fully understood. Once a sporadic adenoma forms, other changes in genetic regulation occur, such as induction of k-ras oncogene and loss of function of tumor suppressor genes on chromosome 18q in the region of the deletion in colon cancer ( DCC) and in pancreatic cancer ( DPC4) genes. Loss of p53 gene function occurs late and is believed to be the defining event that drives the adenoma to carcinoma.

Tumors that arise via the CIN/tumor suppressor gene pathway are typically microsatellite stable (MSS). The remaining 15% of sporadic CRCs arise through the MSI pathway. The MSI pathway involves the primary loss of function of genes that usually repair DNA base-pair mismatches that occur during the normal process of DNA replication in dividing cells. In humans, at least six different proteins ( hMSH2, hMLH1, hPMS1, hPMS2, hMSH6, and hMLH3) comprise the mismatch repair system[ 10]. These proteins form specific heterodimers to coordinate DNA repair and the recruitment of other proteins, such as polymerases and helicases, necessary for mismatch repair. Germline mutations of DNA mismatch repair genes, predominantly hMLH1 (33%) and hMSH2 (31%), are responsible for the familial syndrome of heriditary nonpolyposis colon cancer[ 11]. In addition, approximately 15% of sporadic tumors from the colon, rectum, and other organs demonstrate MSI[ 12]. Interestingly, the most common mechanism causing MSI in sporadic colon cancers is not genetic mutation, but rather transcriptional silencing of hMLH1 as a consequence of methylation of the hMLH1 promoter[ 13].

Epigenetic alterations can also contribute to altered gene expression in colon carcinogenesis. The CpG island methylator phenotype occurs when cytosines in the promoter region of genes become extensively methylated. A number of human cancer genes that contain hypermethylation of promoter CpG islands have been identified[ 14]. These include hMLH, p16 INK4a, and E-cadherin. The process of methylation is an area of intense investigation, and it is anticipated that this line of research should help to define further the molecular pathways involved in CRC in a variety of clinical settings.

Molecular features of CRC in IBD

The neoplastic transformation in IBD is thought to be similar to the adenoma-carcinoma sequence in sporadic CRC (Figure ). However, unlike SCC, where dysplastic lesions arise in one or two focal areas of the colon, in colitic mucosa, it is not unusual for dysplasia or cancer to be multifocal, reflecting a broader "field effect". Many of the molecular alterations responsible for sporadic CRC development also play a role in colitis-associated colon carcinogenesis. The emerging evidence suggests that the two major pathways of CIN and MSI also apply to CACs and with roughly the same frequency (85% CIN, 15% MSI). Distinguishing features of CAC, however, are differences in the timing and frequency of these alterations (Figure ). For example, APC loss of function, considered to be a very common early event in SCC, is much less frequent and usually occurs late in the colitis-associated dysplasia-carcinoma sequence. Conversely, p53 mutations in sporadic neoplasia usually occur late in the adenoma-carcinoma sequence, whereas in patients with colitis, p53 mutations occur early and are often detected in mucosa that is non-dysplastic or indefinite for dysplasia.

Methylation is assuming increasing importance as a mechanism contributing to the genetic alterations in CAC (Figure ). Methylation of CpG islands in several genes seems to precede dysplasia and is more widespread throughout the mucosa of UC patients[ 15].

CRC risk factors

Several factors have been identified which either increase or decrease CRC risk in the setting of IBD (Table ). With respect to increasing CRC risk, the most important factor, reproducibly found across many studies, is the duration of colitis. CRC is rarely encountered before 7 years of colitis. The pooled estimate of cumulative CRC incidence in UC in Eaden's meta-analysis was 2% at 10 years, 8% at 20 years, and 18% after 30 years of disease[ 2]. This may overestimate the risk since many studies in the meta-analysis were from the pre-surveillance era. Thus, a recent study by Rutter et al showed lower cumulative incidence of CRC in patients with UC even at the referral-based St. Mark's Hospital in London: 2.5% after 20 years of disease, 7.6% after 30 years, and 10.8% after 40 years of follow-up[ 16].

Table 1

Factors that increase CRC risk

Longer duration of colitis

Greater extent of colonic involvement

Family history of colorectal cancer

Primary sclerosing cholangitis

Young age of IBD onset (some studies)

Backwash ileitis (possibly)

Severity of histologic inflammation

History of dysplasia

Factors that decrease CRC risk

Prophylactic total proctocolectomy

Regular doctor visits

Surveillance colonoscopy

Chemoprevention

Extent of colitis is an independent risk factor for the development of CRC. The more colonic surface that is involved with colitis, the greater the CRC risk. However, different criteria exist regarding classification of the extent of colitis. Most early reports of surveillance programs used barium enema results at diagnosis as the standard for defining disease extent. A population-based study of over 3000 UC patients in Sweden examined by barium enema demonstrated that patients with proctitis had a standardized incidence ratio (SIR) of 1.7 [95% confidence interval (CI) 0.8-3.2] compared with age-matched population controls without UC, whereas those with left-sided colitis had a SIR 2.8 (95% CI 1.6-4.4), and those with pancolitis had SIR 14.8 (95% CI 11.4 to 18.9)[ 17]. Endoscopic and histologic evidence of inflammation are valid alternative criteria particularly in high risk patients. Very few studies have correlated CRC risk with histologic extent of disease, even though microscopic evidence of colitis is arguably a better indicator of disease extent than either endoscopic or radiographic changes. Mathy et al[ 18] reviewed 30 colectomy specimens and showed that dysplasia and CRC can arise in areas of microscopic colitis that are proximal to areas of gross colitis, suggesting that indeed histologic changes, even without colonoscopic alterations, might better define disease extent for the purposes of cancer risk. Backwash ileitis, defined as pancolitis with superficial involvement of the terminal ileum, has been suggested as an additional increased risk of CRC[ 19], but this requires additional confirmation.

IBD patients with a family history of CRC have at least a two-fold higher risk of CRC[ 20- 22]. Both UC and Crohn's disease patients with primary sclerosing cholangitis (PSC) are at particularly high risk for developing colorectal neoplasia[ 23]. In a population-based Swedish study, the cumulative incidence of CRC in UC patients with PSC was 33% at 20 years[ 24]. By comparing patients with UC with and without PSC, Shetty et al[ 25] reported an adjusted relative risk (RR) for dysplasia or cancer of 3.15 (95% CI, 1.37 to 7.27) in patients with PSC. Current practice guidelines recommend all patients with PSC not previously known to have IBD should undergo a colonoscopy to determine their status. For those patients with IBD, screening and subsequent surveillance should begin at the diagnosis of PSC, and if the patient progresses to the point at which liver transplantation is necessary, prophylactic colectomy should be considered. Young age at onset of colitis has been reported to be an independent risk factor for CRC in some[ 2, 17, 26], but not all studies[ 27, 28]. There is insufficient evidence to support starting screening and surveillance before 8 years of disease in these patients. The severity of colitis has not been considered an independent risk factor for CRC when activity of disease is defined according to the frequency of clinical exacerbations[ 22]. However, a case-control study by Rutter et al showed that increased severity of inflammation, both endoscopically and histologically, correlates with increased frequency of dysplasia[ 29]. It is important to realize that the patient with quiescent IBD is also at increased CRC risk.

With regard to reducing CRC risk, there are two main choices: removing the colon versus conducting a lifelong program of surveillance (Table ). Although prophylactic total proctocolectomy after 7-10 years of colitis would prevent most cancers, it would result in many colectomies that were not necessary and a substantially altered quality of life for patients. Thus cancer prevention in this patient population has focused on periodic surveillance colonoscopies. Surveillance should be viewed as a program that includes regular visits to the doctor, the use of medications to control inflammation (some of which may have chemopreventive effects, see below), and regular colonoscopies. The goal of surveillance colonoscopy is to detect neoplastic lesions before they become biologically dangerous. Thus, the detection and interpretation of dysplasia is crucial to successful surveillance.

DIAGNOSING DYSPLASIA

Macroscopic classification of dysplasia

More recently, we have come to realize that not all types of polypoid dysplasia in patients with IBD carry the same significance. Some polyps may be adenomatous polyps unrelated to colitis and can be managed by endoscopic polypectomy like polyps in the general population[ 38- 40]. One example is the dysplastic polyp encountered in a bowel segment that is entirely free of disease (e.g., in the proximal colon of a patient with left-sided ulcerative colitis). In such cases, one would take the precaution to biopsy the mucosa surrounding the polyp to assure the absence of microscopic disease. Similarly, a dysplastic polyp with a well-defined stalk can be regarded as a sporadic adenoma, even when encountered in a colitic region, if the mucosa lining its stalk is non-dysplastic.

Conservative management is also reasonable for dysplastic polyps that are "adenoma-like"[ 41, 42]. These polyps are endoscopically indistinguishable from sporadic sessile adenomatous polyps, i.e., discrete and ovoid or round, are completely resectable by the endoscope, and are not surrounded by flat dysplasia. Such lesions have long posed a dilemma for endoscopists who were familiar with the DALM concept but reluctant to advocate colectomy for what appeared to be innocuous lesions and possibly nothing more than fortuitous adenomas. Histology has not provided a reliable means of making this distinction in individual cases[ 43], since the histological features of dysplasia in the setting of IBD and in true adenomas can be virtually identical. A 1999 study from The Mount Sinai Hospital in New York reported that conservative management of a cohort of 48 UC patients with a total of 70 such polyps, including 3 with high-grade dysplasia, resulted in no adverse outcomes during a mean follow-up period of 4.1 years[ 41]. Similar conclusions were reached in a concurrent study from Brigham and Women's Hospital[ 42] that was confirmed upon longer follow-up[ 44]. As a result, the burden of deciding whether a polyp qualifies as adenoma-like rests with the endoscopist. Molecular markers may ultimately afford a more objective means of making these distinctions[ 45, 46], but to date, these analyses are not applicable to routine clinical practice.

Microscopic classification of dysplasia

Gastrointestinal dysplasia is defined microscopically as replacement of the native intestinal epithelium by an unequivocally neoplastic, but noninvasive, epithelium[ 47]. It is synonymous with the term "intraepithelial neoplasia" used in other organ systems. A standardized classification system of dysplasia in IBD was established and divided dysplasia into five categories: negative for dysplasia, indefinite for dysplasia, low-grade dysplasia (LGD), high-grade dysplasia (HGD) or invasive cancer[ 47]. A further subdivision of the indefinite category includes probably negative, probably positive, unknown, however many pathologists regard this as optional.

The cellular abnormalities that define dysplasia in IBD are analogous to those characterizing neoplastic tissue in general, namely nuclear abnormalities reflecting inappropriate cellular proliferation and cytoplasmic abnormalities reflecting clonality and aberrant differentiation. The distinction between low- and high-grade dysplasia depends upon the distribution of nuclei within the cells, low-grade dysplasia being characterized by nuclei that remain confined to the basal half of the cells and high-grade by nuclei that are stratified haphazardly between the basal and apical halves[ 47]. Not surprisingly, pathologists are frequently confronted with biopsies that lie in a gray zone between the two categories, and some degree of subjectivity is therefore unavoidable. The diagnostic category "indefinite for dysplasia" is an acknowledgement of the difficulty pathologists face in discriminating between dysplasia and reactive epithelial changes, although experienced pathologists are usually able to discriminate between the two.

There is inconsistency among pathologists in the diagnosis of dysplasia on biopsy. In one study[ 48], there was only 60% agreement for a diagnosis of LGD. Similarly Lim et al[ 49] found that the kappa coefficient for interobserver agreement between ten pairings of five specialist gastrointestinal (GI) pathologists ranged from 0.06 to 0.39. Other studies comparing diagnoses of dysplasia among different pathologists, both prospectively and retrospectively, have concluded that levels of interobserver agreement are fair at best even among specialists in gastrointestinal pathology[ 50- 54]. The best agreement levels tend to occur at the two extremes of negative and high-grade dysplasia and the poorest levels in the two gray zones between low-grade and high-grade dysplasia and on either side of indefinite for dysplasia. From a practical standpoint, it has been recommended that diagnoses carrying serious management implications be reviewed by at least one additional pathologist with expertise in this area[ 55].

BIOLOGY OF DYSPLASIA

Natural history of dysplasia

The natural history of dysplasia is a key factor contributing to the outcome and success of surveillance. The model shown in Figure suggests that colitic mucosa progresses in a systematic fashion: no dysplasia, indefinite dysplasia, LGD, HGD, and finally invasive cancer. Although this is a useful paradigm that facilitates the study of cancer risk markers in IBD, it remains unclear whether dysplasia of one grade may "progress" (or "regress") to another grade. For example, patients undergoing regular colonoscopic surveillance have developed CRC without any prior dysplasia, and it is not necessary for LGD to progress to HGD before cancer arises in the colon[ 30, 56]. This highlights the need to develop markers that are complementary to dysplasia for predicting CRC risk in IBD patients-a subject of ongoing investigation.

In the meantime, we currently rely upon the histological identification of dysplasia to make management decisions. Refinements in interpreting dysplasia based on the 1983 standardized histological criteria[ 47] have enabled a more accurate prediction of which patients are more likely to progress to advanced neoplasia by excluding those whose biopsies only show reactive changes secondary to inflammation. This was amply illustrated by the St. Marks group who found that the 5-year cumulative rate of progression from LGD to HGD or cancer rose from 16% to 54% once biopsies were more precisely reclassified[ 53, 57].

Assuming that early colectomy is not performed, what is the subsequent rate of progression? In the case of patients with HGD, 32% were found to have CRC after some follow-up period[ 37]. For those with LGD, the probability of eventually progressing to HGD or CRC was 16%-29%[ 37]. Data from St. Mark's Hospital indicate that the 5-year cumulative probability of progressing from LGD to HGD or cancer is 54%[ 53]. Strikingly similar results were obtained from The Mount Sinai Hospital, with a 5-year progression rate of 53% among 46 patients with initial flat LGD[ 56]. A recent follow-up analysis from the St. Marks' group indicates slightly lower, but still substantial rates of progression[ 16]. Likewise, a series of 18 patients with LGD followed at the Mayo Clinic demonstrated a 33% 5-year progression rate[ 58]. Despite these rather similar results from three different patient populations, some authors have reported a substantially lower rate of progression. Befrits et al followed 60 patients with flat LGD from the Karolinska Institute in Sweden and found that none developed cancer and only 2 cases of progression to HGD in DALMs over a mean follow-up period of 10 years[ 59]. In the series by Lim et al from Leeds in the U.K., they reported that only 3/29 (10%) patients with LGD progressed to HGD or cancer after 10 years[ 49]. It is worth noting that in the latter two studies, the designation of LGD included specimens that were interpreted prior to the 1983 consensus guidelines, so they might have included cases with indefinite dysplasia.

Because of uncertainty of flat LGD[ 56, 60], these studies have failed to achieve consensus on proper management of flat LGD. Hence, competing options should be discussed with each patient. A patient confirmed to have multifocal flat LGD (2 or more biopsies with LGD from a single screening or surveillance examination) or repetitive flat LGD (2 or more examinations with at least a single focus of LGD), should be strongly encouraged to undergo prophylactic total proctocolectomy. Furthermore, even for patients with confirmed unifocal LGD (only 1 biopsy positive for LGD in a screening or surveillance examination) should also be offered the option of undergoing prophylactic proctocolectomy, since evidence indicates that a 5-year rate of progression to HGD or CRC in this patient group seems to be similar to that of multifocal LGD[ 56].

THE MANAGEMENT OF DYSPLASIA

Once a decision is made to place a patient under surveillance, it is recommended that the patient formally agree to enter such a program and is willing to comply. Patients must be made to understand the limitations of surveillance and accept the concept that despite their own cooperation, dysplasia and cancer can still arise even in the hands of skilled endoscopists and pathologists[ 53].

The best proof that surveillance colonoscopy effectively reduces CRC mortality would be a prospective, randomized, controlled trial in which patients with longstanding IBD would undergo colonoscopic surveillance whereas controls matched for a similar risk profile would not. However, due to ethical, financial and practical limitations, this type of study will likely never come to pass. We must therefore rely on retrospective studies for insights as to the efficacy of surveillance colonoscopy. In a retrospective study by Choi et al, patients with chronic UC who developed cancer were divided into those who had surveillance colonoscopy and those who did not. Patients undergoing surveillance colonoscopy were found to have less advanced Dukes' stage CRC than those who did not and correspondingly had an improved 5-year survival rate (77.2% vs 36.3%, P = 0.026)[ 61]. However, the best evidence that colonoscopy reduces mortality from CRC in UC comes from case-control studies. In one such study, Karlen and colleagues identified 2 of 40 patients with UC and 18 of 102 controls who had undergone at least one surveillance colonoscopy who died as a result of CRC (RR = 0.29), CRC mortality was reduced by as much as 78%, although this did not reach statistical significance[ 62]. Another study found a similar degree of protection[ 22]. In these studies, a protective effect was found for individuals who had even one or two surveillance exams. There is also good evidence from prospective, albeit uncontrolled, studies of surveillance colonoscopy that in general, patients who comply with surveillance have cancers detected at earlier stages compared to those who do not comply[ 53, 63]. Of course, cancers will still arise even within a surveillance program, but in balance, the practice of surveillance is beneficial[ 64].

Although the gastroenterology community has put its faith in surveillance colonoscopy to prevent CRC in IBD patients, surveillance has its limitations. Previous studies have shown low rates of observer agreement for the histopathologic interpretation of biopsy specimens between general pathologists and GI pathologists, or even among expert GI pathologists[ 47, 48]. Endoscopists fail to take a sufficient number of biopsies to exclude the presence of dysplasia or cancer[ 33]. Unlike the dysplastic sporadic adenoma which typically assumes a discrete, polypoid shape surrounded by normal mucosa, dysplasia in the colitic colon can be flat or polypoid and is often difficult to discern. This may be particularly troublesome in a colon that is replete with inflammatory pseudopolyps. Furthermore, there is poor understanding of dysplasia amongst trained gastroenterologists. A survey of practicing gastroenterologists and senior GI fellows in the U.S. found that only 19% of respondents correctly identified dysplasia as neoplastic change[ 35]. Patient drop-out or non-compliance with surveillance contributes importantly to CRC mortality in IBD[ 49, 53] and this must be considered when embarking upon, or continuing, a course of surveillance in individual patients.

RECOMMENDED SURVEILLANCE STRATEGY

Despite the limitations of surveillance colonoscopy, dysplasia remains the best marker for managing cancer risk in IBD. After approximately 7-8 years of colitis, patients should undergo an "initial" surveillance colonoscopy to determine the extent of colitis and check for neoplasia[ 55]. The entire colon should be examined, with approximately 4 biopsies taken every 10 cm. Some experts suggest taking more biopsies in the distal rectosigmoid (e.g., approximately every 5 cm) since the distribution of neoplasia in UC still shows a distal predominance. Biopsies should be taken from flat mucosa, but if any raised or suspicious lesions are encountered, these should be removed if possible and processed in separate specimen containers (with additional biopsies taken near the base of the polyp). If a patient is experiencing moderate-severe colitis symptoms, one option is to control the inflammation medically prior to performing the examination in order to minimize difficulties with the histological interpretation of dysplasia. However, one should not defer the colonoscopy too long, since many expert pathologists now feel that they can readily interpret dysplasia even in the presence of active inflammation.

Figure depicts a recommended surveillance strategy. If no dysplasia is detected, the examination should be repeated in 1-2 years. This interval derives in part from studies reporting that interval cancers can develop within 2 years after a surveillance examination[ 53]. If indefinite dysplasia is reported, the nature of the uncertainty should be discussed with the pathologist. If the suspicion of dysplasia is high (i.e., probably positive), repeat biopsy within 3-6 mo or less may be indicated; if low, the interval can be lengthened to every 6-12 mo. If LGD is detected in a discrete polyp that can be readily resected endoscopically and there is no flat dysplasia immediately adjacent to the polyp or elsewhere in the colon, surveillance can be continued, although the frequency of examinations can be temporarily reduced to every 3-6 mo, particularly to re-evaluate the area of polypectomy. Tattoo of the polypectomy site is advised to permit relocalization of the area on subsequent exams. If LGD is detected in flat mucosa (whether unifocal or multifocal), and is confirmed by a second expert GI pathologist, colectomy should be strongly considered. If the patient refuses, repeat surveillance exams should be undertaken within 3-6 mo or less. However, the patient should be advised that a negative subsequent examination is no assurance of safety, and that temporizing until there is histological progression to HGD or cancer as the indication for colectomy is risky. A patient in whom flat HGD or adenocarcinoma is found and confirmed by two expert pathologists should undergo colectomy unless serious co-morbidities dictate otherwise. If HGD is diagnosed in an adenoma-like polyp but it is completely removed without evidence of flat dysplasia in the adjacent mucosa or elsewhere in the colon, continued surveillance can be entertained. As with any set of recommendations, decisions should be individualized according to the situation of the patient. Hopefully, strategies for surveillance will become more refined as more knowledge of the natural history of dysplasia is obtained.

Patients who have only had small intestinal Crohn's disease without colonic involvement are not considered to be at high risk for CRC. For patients with Crohn's colitis, much less is known. To date, only one practice-based retrospective surveillance study has been reported in patients with Crohn's colitis[ 65]. Of 259 patients with Crohn's colitis affecting at least one-third of the colon for at least 8 years, 16% were found to have dysplasia or cancer over a 16 year period in which 663 examinations were performed, and there were no cancer deaths. While we await additional data on the subject, it seems wise to follow a UC-based surveillance strategy for patients with at least 8 years of substantial Crohn's colitis. An important question that remains to be clarified is whether patients with dysplasia or cancer in the setting of segmental Crohn's colitis can undergo segmental resection of the involved area or should proceed to a more extensive UC-like surgical approach. Another dilemma that is encountered with Crohn's colitis is the management of strictures. This occurs more so than with UC. Finding a stricture in a colon of a patient with UC usually means an underlying malignancy, especially if the stricture is causing symptoms, and is located in the proximal colon[ 66]. However, since most strictures in Crohn's colitis are benign, the patient can often be managed conservatively. Surveillance of such patients often requires using a narrower colonoscope or sometimes dilating a stricture to visualize the proximal mucosa[ 65]. Consideration should be given to adding brush cytology of strictures to regular forceps biopsies, and performing a barium enema to evaluate for colonic wall irregularity.

New endoscopic techniques and molecular screening approaches

Recent publications on chromoendoscopy have demonstrated a greater yield for dye-spray targeted biopsies compared with numerous non-targeted biopsies and thus enhance the endoscopic detection of dysplastic lesions in colitic colons. In a randomized trial by Kiesslich et al[ 67], intraepithelial neoplasia was more than three times as likely to be detected using chromoendoscopy compared with surveillance using nontargeted biopsies (32/84 compared with 10/81; P = 0.003). Rutter et al detected no dysplasia in 2904 non-targeted biopsies in 100 patients, but in targeted biopsies, nine dysplastic lesions were detected, seven of which were visible only with dye spraying by using indigo carmine instead of methylene blue[ 68]. A recent report by Ochsenkuhn et al from Munich, Germany showed a low frequency of colorectal dysplasia in patients with long-standing IBD by fluorescence colonoscopy with 5-aminolevulinic acid[ 69].

Other approaches worth mentioning are to examine the biopsy tissue of patients with IBD for molecular alterations. The best tested of these are aneuploidy, mutations in p53 and ras, and glycosylation abnormalities, particularly increased expression of sialyl Tn antigen (sialyl 2,6 N-acetylgalactosamine)[ 70]. Because the DNA shed into stool should theoretically provide a more comprehensive sampling of abnormal cells than random pinch biopsies, stool DNA testing could potentially contribute to the management of patients with long-standing IBD who are at risk for developing CRC.

Chemoprevention

Despite the relative protection afforded by surveillance colonoscopies in IBD, there are still patients who develop CRC despite seemingly optimal surveillance. This raises the issue of whether chemoprevention in the form of either medications or dietary supplements might help reduce the risk of CRC in IBD[ 71].

In animal models of colon carcinogenesis, ursodiol inhibits carcinogenesis-an effect that may be due to the ursodiol reducing the colonic concentration of the secondary bile acid deoxycholic acid. Ursodiol also has anti-oxidant activity. A study of UC patients with PSC demonstrated that ursodiol use was strongly associated with decreased prevalence of colonic dysplasia[ 79]. This protective effect remained after adjusting for duration of colitis, age at onset of colitis, and sulfasalazine use. In a follow-up to the randomized, placebo-controlled trial by Pardi et al at the Mayo Clinic, 52 patients with chronic PSC and chronic UC (mean 13 years) were followed for a total of 335 person-years. Ursodiol use was associated with a significant protection against the development of dysplasia and cancer (RR = 0.26, P = 0.034)[ 80]. At the present time, however, we do not know whether ursodiol can prevent neoplastic progression in UC patients without PSC.

Recently, there has been interest in the role statins may play as chemopreventive agents in a variety of cancers. In a population-based case-control study of patients who had diagnosis of CRC in northern Israel between 1998-2004, statin therapy was associated with a modest reduction in CRC in the non-IBD population, but a substantial 94% risk reduction in patients with IBD was observed in a subset analysis of a small number of patients[ 81]. Further studies will need to verify this benefit.

Although a single retrospective cohort study suggests that therapy with 6-mercaptopurine is not chemopreventive (or carcinogenic), there remain insufficient data regarding the chemopreventive role of immunomodulators in order to make recommendations and likewise, whether patients who require immunomodulator therapy should continue their 5-ASA therapies[ 74].

Small bowel cancer in IBD

A number of studies have demonstrated an increased risk of developing adenocarcinoma of the small intestine with small intestinal Crohn's disease. Although the absolute number of cases of small bowel adenocarcinoma is low, because of the rarity of this cancer in the general population, the risk is approximately 10-12-fold greater than the general population[ 4, 86]. In the Uppsala study[ 87], the investigators reported only one observed case compared with 0.3 expected cases, but the confidence interval was wide. In the Copenhagen study[ 88], two cases were observed vs 0.04 expected cases, a 50-fold increased occurrence. In the Tel Aviv study[ 89], none of the patients developed small cancer. The material was probably far too small to expect any small bowel cancer cases. In Oxford, a 10-fold increased relative risk was observed for cancer of the small intestine[ 90]. A population-based Swedish study revealed a significantly increased number of cancer of the small intestine (standardized morbidity ratio, 15.64; 95% CI, 4.26-40.06), however, the occurrence of colorectal cancer was not increased[ 91]. Another population-based Canadian study encompassing the years 1984-1997 demonstrated an increased incidence rate ratio of carcinoma of the small intestine (17.4; 95% CI, 4.16-72.9)[ 4].

Other cancers in patients with IBD

Squamous cell carcinoma of the anus has been reported in patients with longstanding, complicated perianal Crohn's disease[ 85]. Worsening perianal symptoms in such patients should warrant heightened vigilance for this tumor which often requires examination under anesthesia for adequate tissue diagnosis.

The risk of hematopoietic cancer in patients with IBD has been a growing concern. Early case series from The Cleveland Clinic[ 96] and The Mount Sinai Hospital[ 99], as well as other centers[ 100] reported an increase in leukemia in patients with UC. A recent large cohort study from Sweden[ 101], which included nearly 50 000 IBD patients concluded this population has a marginally increased risk of hematopoietic cancer, and in UC, lymphoma occurred as expected (SIR 1.0) but myeloid leukemia occurred significantly more often than expected (SIR 1.8). In Crohn's disease, there was a borderline significant increased lymphoma risk (SIR 1.3), essentially confined to the first years of follow up. However, population-based studies from Denmark[ 97], Sweden[ 87] and Canada[ 4] have failed to substantiate any increased risk of leukemia. Likewise, although an increased number of lymphomas have been reported in some case series[ 99, 102], other series[ 96] and several population-based studies[ 87, 91, 97, 98] do not support the notion that patients with UC or Crohn's disease are at increased risk of lymphoma. However, a population-based study from Canada reported an increased rate of lymphoma among male patients with Crohn's disease[ 4].

The risk of lymphoma or leukemia in IBD has raised concerns regarding the lymphogenic potential of immunomodulatory therapy. Following the introduction of tumor necrosis factor inhibitors in the treatment of Crohn's disease, subsequent reports indicated an excess of malignant lymphoma among treated patients[ 103, 104] and raised fears of an iatrogenic lymphoma risk. However, these reports have also highlighted the lack of robust data on the expected occurrence of malignant lymphomas in TNF naïve (but otherwise treated) patients with IBD[ 105- 107]. Studies examining the risk of lymphoma associated with azathioprine (AZA) and 6-mercaptopurine (6-MP) have yielded variable results. Heterogeneity in the type, dose, and duration of immunomodulatory therapy may be responsible for this discrepancy. A few studies with suboptimal dosing failed to demonstrate an increased risk of lymphoma[ 4, 108- 112]. In contrast to these reports, other studies have demonstrated an increased risk of lymphoma after purine analog therapy[ 113- 115]. In one such study, Kandiel et al reported a 4-fold-higher risk of lymphoma inpatients treated with AZA or 6-MP compared with the general population[ 114]. Another recent study showed a statistically significant increase in the development of malignancies among IBD patients treated with 6-MP who developed sustained leucopenia[ 115].

FUTURE DIRECTIONS

The future looks promising with respect to new developments in the management of cancer risk in IBD. Chromoendoscopy is likely to be used more for management, but whether the predictable increase in the yield of dysplasia will alter the overall natural history remains to be studied. In the modern era of molecular diagnostics, tissue and even stool samples of patients with IBD can be investigated for molecular alterations. For example, University of Washington investigators have demonstrated that because there is often widespread genomic instability throughout the colon of IBD patients, it may be possible to analyze rectal biopsies by DNA fingerprinting or fluorescence in situ hybridization methods[ 116] to identify patients at particularly high risk. The advent of technology to extract human DNA from stool and look for specific DNA mutations associated with sporadic colon carcinogenesis[ 117, 118] implies that a similar approach may also be worthwhile in IBD patients. It is anticipated that refinements in our knowledge of cancer biology, clinical practice, and molecular discovery will bring a new level of sophistication to the management of patients with longstanding IBD and lower the incidence of CRC in this high-risk population.

Footnotes

S- Editor Liu Y L- Editor Alpini GD E- Editor Li JL

References

1. Crohn BB, Rosenberg H. The sigmoidoscopic picture of chronic ulcerative colitis. Am J Med Sci. 1925;170:220-228. [ Google Scholar]

# data[].attributes.attachment_link.description
Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis.

# data[].attributes.headline
Seonwook Kim: Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease

# data[].attributes.subject
Seonwook Kim: Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease

# data[].attributes.body
My selected article demonstrates how self-tunable engineered yeast probiotics treat inflammatory bowel disease (IBD). The study is important because this new approach provides a new therapeutic platform advantage over most available IBD therapies that suppress the immune system systemically and possibly increase the risk of infections and some cancers. One of the key findings is that CRISPR-Cas9 engineered yeast delivers a probiotic-based dynamic anti-inflammatory response in the inflamed tissue microenvironment through P2Y2-RROP1 gene circuit responsive to extracellular ATP(eATP). eATP signals upregulate pro-inflammatory cytokine production and effector T-cell activation, suppress regulatory T cell responses in IBD. These yeast probiotics suppressed intestinal inflammation in mouse models of IBD, reducing intestinal fibrosis and dysbiosis with high efficacy. As a nutritional science approach, it uses Saccharomyces yeast species which have long been known for use in foods and its anti-inflammatory response may help IBD patients to absorb more nutrients through GI tract. As a clinical implication, the modulation of intestinal pro-inflammatory and anti-inflammatory balance with engineered yeast probiotics may provide generalizable therapeutic approach for intestinal inflammation.

Scott, B.M., Gutiérrez-Vázquez, C., Sanmarco, L.M. et al. Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease. Nat Med 27, 1212–1222 (2021). https://doi.org/10.1038/s41591-021-01390-x
Full article available at uky library.

# data[].attributes.headline
Duration of Breast-Feeding and Celiac Disease Development

# data[].attributes.subject
Duration of Breast-Feeding and Celiac Disease Development

# data[].attributes.body
(Ellen Reusch) For this week's wall, I found an article from the World Journal of Gastroenterology discussing the effect the timing of gluten introduction might have on the development of celiac disease. This paper analyzed results from several other, some older, studies on the duration of breastfeeding and whether it had an impact on the development or timing of celiac disease occurring in children. Several studies had previously documented a negative correlation between the duration of breastfeeding and the development of celiac disease, and this review concluded that there are still plenty of questions regarding breastfeeding's relationship with celiac disease development. This epidemiological data, however, was used by the ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) to recommend that parents introduce their children to gluten between the ages of 4 months and 7 months, and in small amounts gradually while still supplementing with breastfeeding. I think this article relates to our week 2 required readings as those focused on not only celiac's disease, but also some of the predispositions nutrition may play in a person's likelihood to develop the autoimmune condition. Additionally, this paper directly relates to nutrition as it discusses how early nutritional sources play a role in a child's future gastrointestinal health.  Some of this data could be used to change how new mothers decide between breastfeeding and formula-feeding their newborn babies, when they have a choice.

# data[].attributes.headline
Circadian Rhythm's Involvement in Irritable Bowel Diseases

# data[].attributes.subject
Circadian Rhythm's Involvement in Irritable Bowel Diseases

# data[].attributes.body
The reason this article first grabbed my attention was the connection between melatonin and inflammatory bowel diseases. Melatonin supplements is something that I take periodically to help with sleep. However, I didn't realize the beneficial properties of melatonin. This study is important because it points to a potential cause of these irritable bowel diseases and could become a potential therapeutic for treating patients. One of the most prominent negative symptoms associated with IBD is poor quality of asleep. Poor quality of asleep can exacerbate inflammatory cytokines thus negatively impacting the GI function which in turn can result in a positive feedback loop maintaining perpetual inflammation. One key finding that I would like to mention from this study is that they looked at a DSS mice model with colitis and they disrupted the circadian rhythm in one group and kept it consistent in the other. They found that that the group with the disrupted circadian rhythm had a more severe form of colitis, significant weight loss and a higher mortality. This just emphasizes the significant role that the circadian rhythm may play in IBD. This information relates to nutritional sciences because we can get melatonin from our food (bananas, tomatoes, and strawberries). Melatonin can help to regulate our circadian cycle and potentially help alleviate these symptoms. As I alluded to earlier, there is still a lot of research to be completed on this to see if it would be a viable therapeutic for individuals who have IBD.  However, if it is seen as a viable therapeutic, we could use it to treat patients and help modulate their inflammation keeping their flare ups to a minimum.

-By Ashley Wahlman

Citation:
Swanson, G. R., Burgess, H. J., & Keshavarzian, A. (2011). Sleep disturbances and inflammatory bowel disease: a potential trigger for disease flare?. Expert review of clinical immunology, 7(1), 29–36. https://doi.org/10.1586/eci.10.83

# data[].attributes.attachment_link.title
Sleep disturbances and inflammatory bowel disease: a potential trigger for disease flare?

# data[].attributes.attachment_link.description
Inflammatory bowel disease (IBD) is a waxing and waning disease characterized by diarrhea, abdominal pain and weight loss. Recently, there has been an increased interest in the roles that sleep, circadian rhythms and melatonin could have as regulators ...

# data[].attributes.body
The research paper that I selected this week for the module was titled Accuracy of Serologic Tests and HLA-DQ Typing for Diagnosing Celiac Disease. I found this paper to be quite an important read because it directly related to my line of work. (Which is testing for HLA DQ2/DQ8 genotype from whole blood specimens in the laboratory). This is to report a positive or negative resort to be reviewed by pathologists and physicians. The study brought to light a whole lot of what goes on behind the scenes of DQ2/DQ8 testing, which happens to be small-bowel biopsies from patients. This study even included small-bowel histologic findings (photographs) which were very neat to look at. This report related directly to nutritional sciences because it brought up how patients were to be biopsied and seen before they started their gluten free diet and then biopsied once again months and months later to report the difference the diet makes in the lining of the bowel. The clinical implications of this study were that they reported that there is an association with HLA DQ2/DQ8 with celiac disease and the sensitivity could vary with the patient. The study suggested that the absence of HLA DQ2/DQ8 excludes the diagnoses of celiac disease although a positive result for this genotype is not enough to confirm the disease either.

Citation:
Hadithi, M et al. “Accuracy of Serologic Tests and HLA-DQ Typing for Diagnosing Celiac Disease.” Annals of internal medicine 147.5 (2007): 294–302. Web.

# data[].attributes.body
The research paper I selected for this week is titled Prevalence of Celiac Diseases in 52,721 Youth With Type 1 Diabetes: International Comparison Across Three Continents. As it can be assumed from the title, this study was performed to examine the prevalence of Celiac Disease (CD) and type 1 diabetes (T1D), but it mostly examined the differences between the youth who had both CD and T1D versus the youth who only had T1D. This study is important because it looks into the relationship of two common chronic diseases. It is also important because it attempts to account for differences worldwide, possibly uncovering more differences than they would have found by only examining one place. There are two key findings from this study that I want to mention. The first is that very few of the youth with CD and T1D were deemed overweight. This ties in with nutritional science through our learnings that CD (and other inflammatory bowel diseases) are associated with symptoms of weight loss, which helps explain why most of the youth with CD and T1D were at a lower weight than the youth who only had T1D. The other finding I wanted to mention is that youth with CD were typically diagnosed with T1D at an earlier age (avg. of 5.4 yrs. old) than youth only being diagnosed with T1D (avg. of 7 yrs. old). This relates to nutritional sciences as well because it shows that there could be a common denominator for diseases like CD and other chronic conditions like diabetes, provided that more research is done between the relation of the two diseases. A clinical implication from this trial is that more patients with T1D should be tested for CD as well, since the study found that many of the patients with CD and T1D had asymptomatic CD, meaning it could be under-detected/under-diagnosed in patients that are currently only diagnosed with T1D.

Craig, M. E., Prinz, N., Boyle, C. T., Campbell, F. M., Jones, T. W., Hofer, S. E., Simmons, J. H., Holman, N., Tham, E., Fröhlich-Reiterer, E., DuBose, S., Thornton, H., King, B., Maahs, D. M., Holl, R. W., & Warner, J. T. (2017). Prevalence of celiac disease in 52,721 youth with type 1 diabetes: International comparison across three continents. Diabetes Care, 40(8), 1034–1040. https://doi.org/10.2337/dc16-2508

# data[].attributes.attachment_link.readable_text
Maria E. Craig, Nicole Prinz, Claire T. Boyle, Fiona M. Campbell, Timothy W. Jones, Sabine E. Hofer, Jill H. Simmons, Naomi Holman, Elaine Tham, Elke Fröhlich-Reiterer, Stephanie DuBose, Helen Thornton, Bruce King, David M. Maahs, Reinhard W. Holl, Justin T. Warner, on behalf of the Australasian Diabetes Data Network (ADDN), the T1D Exchange Clinic Network (T1DX), the National Paediatric Diabetes Audit (NPDA) and the Royal College of Paediatrics and Child Health, the Prospective Diabetes Follow-up Registry (DPV) initiative; Prevalence of Celiac Disease in 52,721 Youth With Type 1 Diabetes: International Comparison Across Three Continents. Diabetes Care 1 August 2017; 40 (8): 1034-1040. https://doi.org/10.2337/dc16-2508

Download citation file:

# data[].attributes.attachment_link.title
Prevalence of Celiac Disease in 52,721 Youth With Type 1 Diabetes: International Comparison Across Three Continents

# data[].attributes.attachment_link.description
Maria E. Craig, Nicole Prinz, Claire T. Boyle, Fiona M. Campbell, Timothy W. Jones, Sabine E. Hofer, Jill H. Simmons, Naomi Holman, Elaine Tham, Elke Fröhlich-Reiterer, Stephanie DuBose, Helen Thornton, Bruce King, David M. Maahs, Reinhard W. Holl, Justin T.

# data[].attributes.body
Click the pink plus sign at the lower right-hand side of the screen to get started!  Please email me with any questions about this exercise. -Dr. Police