Sticky Paediatric IBD - Articles and Research

Results: Twenty-five cases of HSTCL were identified. Twenty-two (88%) patients had inflammatory bowel disease and three had rheumatoid arthritis. Four cases (16%) were in women and four patients were above 65 years of age. Twenty-four cases (96%) also received an immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate). Two patients received adalimumab alone.

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Conclusion: HSTCL is no longer restricted to the previously identified risk group of young male patients, but can also occur in patients with rheumatoid arthritis, females and older adults receiving TNF-α inhibitors and immunomodulators. Improved disease outcomes using combination therapy should be tempered by the risk of developing HSTCL.

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Inflammatory bowel disease (IBD) includes Crohn disease (CD) and ulcerative colitis
(UC), and is often diagnosed in late childhood and early adulthood. IBD is thought
to develop as a result of dysregulation of the immune response to normal gut flora
in a genetically susceptible host. Approximately 25% of incident cases of IBD occur
during childhood and the rest occur throughout adulthood, peaking in the second
and third decades of life. What determines the age of onset remains unexplained.
Studying early-onset presentation and epidemiology of complex predominately adult
diseases such as IBD is particularly necessary, as the early onset may represent the
‘‘pure’’ form of the disease process and hence may hold secrets of the initiating events
of IBD pathogenesis. Basic, translational, and clinical scientists continue to focus on
pediatric IBD, because it may shed light not only on the cause but also the prevention
of this lifelong disease. Over the last decade, data from pediatric IBD studies have
demonstrated many similarities and differences between pediatric and adult onset,
which continue to add pieces to an increasingly complex IBD puzzle. The mechanism
responsible for these similarities and differences remains unanswered.
The purpose of this article is to discuss clinically relevant epidemiology and treatment
aspects of pediatric IBD, with a special focus on similarities and differences in
pediatric and adult IBD. Epidemiologic similarities and differences may ultimately
provide the link to a better understanding of the pathogenesis of IBD. This article
also highlights evidence-based treatment algorithms, with special focus on pediatric
studies and care for children.

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Over the last some years the increasing knowledge on the pathogenesis of Crohn's disease led to the development of a number of biological agents targeting specific molecules involved in gut inflammation, first of all TNF-alpha and its receptors. Infliximab, adalimumab and certolizumab have been successful in inducing and maintaining remission in Crohn's disease at both short and long term. This was recently confirmed by a Cochrane meta-analysis and also open label extension follow-up and cohort studies. Emerging new data however indicate that combination therapy with infliximab-azathioprine appears to have added benefit in inducing steroid-free remission and mucosal healing than either infliximab or azathioprine alone in azathioprine-naïve patients with early disease. Similarly the combination of steroids induction and infliximab was efficacious in luminal Crohn's disease. In contrast, there seems to be no synergism between methotrexate and infliximab. It is also less clear whether it is beneficial to use short or long-term infliximab-azathioprine combination in patients who previously failed therapy with azathioprine. In contrast, combination may potentially be associated with increased risk for infection and cancer. In case control-studies, especially the combination of steroids and anti-TNF and older age increased the risk for infectious complications, while scattered case reports point to the potentially increased risk of a rare form of non-Hodgkin's lymphoma (Hepatosplenic T cell lymphoma) with the use of azathioprine-anti-TNF combination. The aim of this review is to summarize the benefits and risks for the use combination therapy with TNF-alpha inhibitors in the treatment of Crohn's disease.

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Conclusions: More than half of children diagnosed with CD present with ileocolonic disease. Patients with disease involvement of the terminal ileum are more likely to present with stricturing disease complications, indicating a particular surveillance and treatment strategy. The Paris classification is a useful tool to capture the variety of phenotypic characteristics of paediatric CD.

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Background: Jejunoileitis (JI) is an unusual manifestation of Crohn’s disease (CD) that has been associated with high morbidity and the frequent need for surgical intervention. Although the disease has been well-described in adults, the true prevalence and clinical phenotype in children is unknown.
Aim: To compare the clinical course and nutritional impact of CD in children with and without proximal small bowel involvement.
Methods: Patients with either Crohn’s jejunitis or JI with or without colonic involvement were identified through a clinical database (1996–2002). All radiologic studies were reviewed by an experienced radiologist blinded to the clinical diagnosis. Thirty-six patients with CD without histologic or radiologic signs of proximal small bowel involvement were used for comparison. All medical, surgical, and hematologic parameters were compared in both disease groups.
Results: Among the 134 patients with CD, 23 (17%) had radiologic signs of JI, including intestinal fold thickening (57%), luminal nar- rowing (31%), and skip lesions (13%). Enteric fistula (6%) and stric- tures (6%) were less common. Patients with JI were likely to be stunted at the time of diagnosis, require surgical intervention (P < 0.03) and nutritional therapy in the form of nasogastric tube feeds (P < 0.03). Nutritional therapy was also associated with an improvement in height in patients with proximal small bowel disease (OR:5.87).
Discussion: JI is a relatively common disease phenotype in children with CD that requires aggressive nutritional and surgical intervention. Future studies are required to determine if the early detection and use of immune modulators may lessen the morbidity associated with proximal small bowel disease

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Background. Delayed growth is a well-established feature of pediatric Crohn's disease. Several factors have been shown to affect growth, including disease location, severity, and treatment. The recently discovered NOD2 gene has been correlated to ileal location of Crohn's disease and subsequently could affect growth through the resulting phenotype or as an independent risk factor. The aim of our study was to determine if growth retardation is affected by genotype independently of disease location or severity.

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Differentiating Crohn's disease from UC and IBDU is vital for children. Appreciable phenotypic differences exist between adult and paediatric-onset Crohn's disease (PCD) at diagnosis. Guidelines (JPGN 2010;50:S1–S13) for PCD diagnosis recommend assessment by upper-gastrointestinal endoscopy (UGIE), colonoscopy with terminal ileal (TI) biopsy and small-bowel imaging (SBI). We aimed to establish the relative contribution of each part of evaluation to PCD diagnosis

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Immune responses to microbial antigens are associated with more aggressive disease phenotypes among children with Crohn's disease, reports the latest issue of the American Journal of Gastroenterology.

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Objectives: Variation in medical care can be a barrier to improving clinical outcomes. We aim to describe the variation in care of Crohn disease as provided by a broad sample of pediatric gastroenterologists.

Methods: Two hundred forty-six Crohn disease patients of 93 pediatric gastroenterologists from 48 practice sites starting treatment with either thiopurine or infliximab were studied. We assessed variation in diagnostic testing that had been performed to establish the diagnosis of Crohn disease and to assess the phenotype, extent, and severity of disease. We also assessed variation in initial thiopurine and infliximab dosage and in nutritional therapy.

Results: Diagnostic studies in which care was uniform included complete blood count, performed in 100% of patients, erythrocyte sedimentation rate and colonoscopy in 96%, and upper endoscopy in 89%. However, imaging of the small bowel had not been performed in 19%, and a stool test for pathogens had not been performed in 29%. Thiopurine methyltransferase (TPMT) had been measured in 61% of patients before treatment with a thiopurine; in 85%, TPMT was normal. Nonetheless, even when TPMT was normal, 40% of patients received an initial dose of thiopurine that was lower than recommended. Testing for tuberculosis before initiating treatment with infliximab was not performed in 30%. In addition, 36% of severely underweight patients were not receiving a multivitamin supplement, supplemental formula, or tube feeding.

Conclusions: There is variation in diagnostic and therapeutic interventions in the management of pediatric Crohn disease, and gaps exist between recommended and actual care. JPGN 49:297–303, 2009. "

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Abstract
Approximately 20% of all inflammatory bowel disease (IBD) first presents in childhood or adolescence, and approximately 10% of the estimated 1.4 million Americans with IBD are under age 17. Diagnosis in pediatric patients may be complicated at presentation due to atypical symptoms and/or extraintestinal manifestations (eg, short stature, chronic anemia, unexplained fever, arthritis, mouth ulcers). Pediatric IBD is traditionally diagnosed using endoscopic evaluations of the upper and lower gastrointestinal tract with mucosal biopsies for histologic confirmation. Less invasive serologic testing for IBD may be particularly valuable in pediatric patients, particularly given the association between serum immune reactivity and severe disease phenotypes that is drawing increasing attention. These serologic markers may help stratify risk and identify appropriate pediatric candidates for early aggressive therapy. Serologic testing in pediatric patients includes traditional IBD serologic markers such as anti–Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibody, as well as newer antimicrobial antibodies, including antibodies to outer membrane porin C; I2, a bacterial sequence derived from Pseudomonas fluorescens; and CBir1 flagellin, a colitogenic antigen of the enteric microbial flora in C3H/HeJBir mice strain. Given recent data associating seropositivity with aggressive clinical phenotypes and rapid disease progression, serologic testing may allow early initiation of therapy, maintenance of remission, reduction of corticosteroid exposure, facilitation of mucosal healing, and restoration of normal growth velocity.
Keywords: Inflammatory bowel disease, diagnosis, serologic markers, pediatric, phenotypes, prognostic, biologic therapy

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Lymphoma Risk in Children with Inflammatory Bowel Disease

Due to the early age of immune suppression exposure in children with inflammatory bowel disease (IBD), there is concern that such medication may lead to an increased risk of malignancy. This possibility is especially concerning as there is an increased risk of hepatosplenic T-cell lymphoma in children with IBD in young males who are receiving thiopurines with or without the addition of anti-tumor necrosis factor (TNF) antibodies.

The authors of this study retrospectively evaluated a large IBD data set over a 30-year period to determine actual patient risk. This study was comprised of 1560 study subjects from 1979 to 2009 who were treated at a single-pediatric tertiary care center with expertise in IBD. Follow-up time of all patients after an initial diagnosis of IBD was calculated in months up until their current visit or until they left the practice. The amount of time of treatment for IBD for all medication classes, including thiopurines and anti-TNF antibodies was also calculated.

In order to determine medication risk, “Patient-years taking medications” was used to determine the total number of years that patients were treated with specific medical therapies. “Patient-years observed” was used to determine the aggregate number of months a patient was exposed to a specific medical therapy.

In total, 1374 patient charts qualified for analysis. There was a mean follow-up of 4.8 ± 3.4 years per patient with 58% of patients having Crohn disease, 39% having ulcerative colitis, and 3% having inflammatory bowel disease unclassified. A thiopurine agent was used in 61% of patients, and 22% of patients were treated with an anti-TNF antibody. When all patients were considered, only 2 cases of lymphoma were identified in follow up visits. Both patients were males (12 and 18 years of age), and both were receiving thiopurine treatment. Both patients were treated with chemotherapy and were alive after treatment. A third patient receiving thiopurine therapy was diagnosed with EBV-related hemophagocytic lymphohistiocytosis, and the disease was successfully treated with discontinuation of the thiopurine. This data helped determine a risk of two lymphomas per 2574 patient-years if patients were actually taking this medication, and a risk of two lymphomas per 4441 patient-years if a patient had ever taken a thiopurine. The absolute incidence rate of lymphoma in children receiving thiopurines was 3 per 10,000 patient-years. Of note, no lymphomas were noted in any patient receiving anti-TNF antibody therapy. This absolute incidence was compared to the National Cancer Institute Surveillance Epidemiology and End Results database which showed an incidence lymphoma rate of all children 19 years or younger of 4.5 per 10,000 patient-years in children receiving thiopurines and of 0.58 per 10,000 patient-years in all children.

This study suggests that the risk of lymphoma development was low in this study in a manner similar to other studies although the results were not statistically significant. There appears to be a slight risk of lymphoma development in children with IBD receiving thiopurines in which the causes (such as genetic risk factors) need to be further elucidated.

(Ashworth L, Billett A, Mitchell P, Nuti F, Siegel C, Bousvaros A. “Lymphoma risk in children and young adults with inflammatory bowel disease: analysis of a large single-center cohort.” Inflammatory Bowel Diseases. 2012: 18: 838-843).

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Prometheus Launches New Monitoring Test To Help Guide Inflammatory Bowel Disease Management

PROMETHEUS® Anser ™ IFX designed to help identify potential causes for loss of treatment response among

IBD patients using infliximab

SAN DIEGO, PRNewswire – Prometheus Laboratories Inc., a specialty pharmaceutical and diagnostic company, announced today the market launch of its proprietary new generation monitoring test, PROMETHEUS Anser IFX. This test measures drug (infliximab) and drug antibody levels in one sample among inflammatory bowel disease (IBD) patients using infliximab – helping physicians identify potential causes for loss of treatment response and helping to guide patient management decisions. This is the first commercial test utilizing Prometheus' proprietary homogenous mobility shift assay (HMSA) platform technology. Prometheus intends to use this platform for subsequent introductions of additional tests targeted to other biologic agents being used to treat a variety of autoimmune diseases.

The Crohn's and Colitis Foundation of America estimates that approximately 1.4 million Americans suffer from IBD. Approximately 50% of IBD patients using infliximab may eventually experience a loss of treatment response during their treatment. For some patients, this loss of treatment response may be the result of insufficient infliximab levels. For others, the loss may be due to the development of antibodies to infliximab (ATI). If the loss of treatment response is due to the development of ATI, increasing the infliximab dose – the most common first step for physicians – may be less effective than switching to another treatment agent. PROMETHEUS Anser IFX test was verified with more than 3,000 IBD clinical patient samples.

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Approximately 25% of patients with inflammatory bowel disease (IBD) have the onset of their disease within the first 2 decades of life. Malnutrition is frequent in patients with IBD, especially those with Crohn's Disease (CD). Various micronutrient deficiencies also contribute to morbidity in these patients. Liquid nutrition is frequently utilized to manage the group of patients with malnutrition. In pediatric CD, there is considerable evidence to support the use of polymeric formula as exclusive nutrition to induce remission in newly diagnosed patients, as well as in those with relapses. Exclusive enteral nutrition is an attractive alternative to corticosteroids in patients with CD. There is no evidence for using exclusive enteral nutrition for inducing or maintaining remission in patients with UC. We review the nutritional aspects of patients with IBD and the use of liquid enteral nutrition for remission induction in pediatric patients with IBD

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A definition of growth impairment in terms of a static height measurement may be misleading, since it is influenced by parental height and pubertal status. A patient may be normally short; conversely a previously tall child may not have grown for 2 years but may still be of average stature for age and gender. Serial measurements showing a fall from higher to lower percentiles and height velocity expressed as a z-score for age and gender should be used to define growth faltering. Height velocity z-score for age and gender is the most sensitive parameter to recognize impaired growth. One of the drawbacks of height velocity is that normal standards for height velocity throughout childhood are based on height increments during 12-month periods. It is recommended that height velocities be calculated over intervals no shorter than every 6 months. A height velocity z-score of-2 over a 12-month period equates to a reduction in height z-score of approximately 0.3 to 0.4. It should be noted that BMI may not be a reliable marker of nutrition status in pediatric IBD; it does not reflect alterations in body composition (i.e., decreased skeletal muscle). Thus, BMI can underestimate malnutrition in patients with inflammatory bowel disease (9). Recent evidence has shown that children with CD have decreased fat-free mass 2 years after diagnosis, even in those patients with clinical improvement (including weight gain), suggesting that weight gain was mainly due to an increase in fat mass.

Impaired linear growth is defined by at least one of the following criteria: (10)

1. Height z-score at diagnosis or subsequently significantly less than expected height z-score

• Difference between observed height z-score and predicted height z-score using the ‘Mid-parental Heights’ formula is >2.0 OR

• Difference between observed height z-score and the ‘pre-illness' height z-score is >1.0

2. Current height z-score significantly less than height z-score at diagnosis or reduction in height z-score since diagnosis is < 0.75

Assessment of pubertal status by Tanner staging should be an integral part of nutrition and growth assessment in patients with IBD. Self-assessment using line drawings and written descriptions of Tanner stages have been validated in children with CD (11). In girls, menarchal status should also be ascertained. Females enter the adolescent growth spurt relatively early in puberty, while in males it occurs late (Tanner 4). The growing phase could be considered final once they have entered Tanner stage 5 and they have demonstrated less than 0.5 cm linear growth in 12 months.

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Asthma

The lifetime asthma prevalence in the United States per 2010 CDC survey is approximately 13.5% (18). Asthma therapy is typically based on the frequency, severity, and time of day of asthma symptoms. Mainstays in the therapy of asthma include both short and long acting inhaled beta 2 adrenergic receptor agonists (albuterol, salmeterol), anticholinergics (ipratropium), inhaled glucocorticoids (budesonide, fluticasone), leukotriene receptor antagonists (montelukast), theophylline, and anti IgE therapy (omalizumab). Using the Lexi-Comp and Epocrates databases interactions between Asthma and IBD medications were evaluated. Medications evaluated for IBD include prednisone, 5-ASA, mercaptopurine, azathioprine, infliximab, and methotrexate.

Interactions between these drug classes include an increased risk of hypokalemia with prednisone and either long or short acting beta 2 receptor agonists. The combination of infliximab and theophylline may lead to decreased levels of theophylline levels due to altered hepatic metabolism. Methotrexate should be avoided in these patients do to the increased risk of pulmonary fibrosis. Finally a significant side effect was noted between the combination of methotrexate and theophylline. Used in conjunction these medications may increase theophylline levels and decreases methotrexate levels.

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Abstract
Growth retardation (GR) may pose a significant challenge to the quality of life and the proper management of children and adolescents with Crohn's disease (CD). It can occur in a significant proportion of patients, and may precede clinical evidence of bowel disease. Current evidence suggests that GR is a complex interaction between nutritional status, inflammation, disease severity, and genotype, which causes resistance to the effects of growth hormone. Recent research has identified a key role for the inflammatory cytokines TNF alpha, IL-6, and IL1 beta. This review summarizes current knowledge as well as gaps in our understanding of the mechanisms involved and the usefulness of the different treatment modalities in promoting growth in CD patients.

(Inflamm Bowel Dis 2007)

Crohn's disease (CD) in children and adolescents is a complex disorder with a relapsing course that can be very difficult to manage for patients and physicians alike. Like adults, children and adolescents are prone to the same diverse array of complications stemming from the disease and its therapy, with the exception of growth failure and delayed puberty. These complications occur primarily in pediatric onset CD, and may pose a significant challenge to the quality of life and the proper management of these children. With our expanding therapeutic options for induction and maintenance of remission, GR often remains the most vexing and significant source of consternation for patients and care takers alike. This article provides a review of the physiologic determinants of normal growth and a literature-based review of potential risk factors for GR in children and adolescents with CD. These factors include the inflammatory process, disease severity and location, nutritional state, drugs, and genes. We will also discuss the evidence for medical, nutritional, and surgical interventions on growth.

Growth failure occurs in 15%–40% of children with inflammatory bowel disease (IBD)1 and growth failure may precede clinical evidence of bowel disease by a few years.2 Growth failure is less common in ulcerative colitis (UC) compared to CD both at diagnosis and during follow-up.1, 3 In CD, temporary growth failure occurs in 40%–50% of affected children2 and stunting into adulthood may persist in 15%–30% of patients.4, 5 In 1 study of 105 children with CD admitted to hospital during 1968–1983, it was shown that despite GR in the teenage years, most young people with IBD eventually achieved normal height.6 Many studies, however, have found that height at maturity is often compromised.3 Hildebrand et al,7 in a study following 128 IBD patients longitudinally from childhood to adulthood, suggested that up to 25% will not achieve their growth potential. Furthermore, final height remains below the 5th percentile in 7%–30% of patients.5, 7, 8–10 Sawczenko et al8 recently conducted a retrospective review of 123 adult patients with disease onset below age 16. They reported a more modest deficit, and found that 19% of these adults had achieved a final height below their target height.

Normal linear growth occurs via activation of the growth hormone (GH) insulin-like growth factor 1 (IGF-1) axis while supported by an adequate supply of nutrients. GH secreted from the pituitary gland stimulates the release of IGF-1. IGF-1 stimulates the proliferation and hypertrophy of chondrocytes in the epiphyseal growth plate, resulting in growth of the long bones (Fig. 1). Circulating IGF-1 is found in complexes with high-affinity IGF binding proteins (IGFBPs). There are at present 6 known IGFBPs. Most serum IGF-1 binds to IGFBP-3, which in turn is regulated by GH. The binding protein IGFBP-1 is regulated primarily by insulin levels, but also by corticosteroids. IGFBP-1 expression is increased in states of insulopenia and starvation and by corticosteroids in a dose-dependent manner.11, 12 Factors that increase IGFBP-1 may decrease the availability of bioactive IGF-1.

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TREATMENT STRATEGIES
Enteral Nutrition and Growth
Enteral nutrition has been shown to promote and restore growth in pediatric CD. Sustained enteral nutrition (EN) may promote growth through several pathways: by inducing remission, by supply of micro- and macronutrients as well as calories required for growth, or by decreasing circulating cytokines. In an important study, Banerjee et al52 prospectively investigated the effect of polymeric EN on inflammatory markers and indices of nutritional restitution in children with active CD. They found a decrease in circulating IL-6 by day 3 of the study. A decrease in serum CRP, IL-6, and an increase in serum IGF-1 were noted by day 7, while measures of nutritional improvement occurred only from day 14. Of note, this important study included a small cohort that was not growth retarded, the baseline IGF-1 concentrations were not very low, and consistent marked improvement was noted from day 14. Given the small number of patients involved and fluctuations noted until day 14 in the median and range of IGF-1, more data are required before it can be established that an early elevation in IGF-1 is not due to an increase in protein and caloric delivery. Two additional studies evaluated the effect of EN on IGF-1. One supported a rise in IGF-1 by day 14 and the other did not.34, 53 Thus, at present, the mechanism by which EN affects growth remains to be determined.

A recent Cochrane review established that, despite the paucity of controlled, well-designed studies, current evidence indicates that EN may be superior to corticosteroids for achieving an increase in height velocity.1 In a small but randomized controlled study of 24 children with active CD, high-dose steroids (prednisolone 2 mg/kg/day for 2 weeks, maximum 60 mg/day, reduced based on clinical response) were compared to an elemental diet given exclusively for 4 weeks.54 In that study there was a similar improvement in disease activity and duration of remission in both groups, regardless of the site of disease. Nevertheless, subsequent growth velocity was significantly better in the group treated with the elemental diet (+0.3 ± 3.3) compared to the corticosteroid group (−3.1 ± 2.8), despite a greater and more sustained increase in energy intake in the group treated with steroids. Similar results were obtained in 2 more studies.55, 56, 57 In the only meta-analysis of pediatric studies58 including nonrandomized studies and abstracts, EN was found to have a significant effect on height velocity standard deviation scores compared to steroid treatment. One reason that sustained EN may lead to better short-term growth over steroids may have to do with a superior improvement in lean body mass (which is associated with an increase in IGF-1), while steroids may preferentially increase fat accretion.17 A single study has shown that corticosteroids increase circulating IGF-1 blood levels during treatment of active disease in an adult population.33 Of note, free IGF-1 did not return to levels noted in a control population. More data are required in order to evaluate or compare the effect of corticosteroids on IGF-1 and growth in children.

Enteral nutrition (polymeric or elemental formulas) can induce remission in CD patients.58, 59 In adults, remission rates are higher with steroids compared to EN, while in children data are conflicting,54, 58 with 1 meta-analysis showing that steroids and EN result in similar remission rates.58 EN may have an effect on growth even after remission was achieved.10, 60 Thus, the effect of EN on growth is most likely the result of the combined effects of improved nutrition on GH IGF-1 axis, effect of EN on inflammation, and direct effect that nutrition might have on linear growth.

Since low caloric intake often contributes to growth failure, it is reasonable to assume that oral nutrition supplementation increases caloric intake. However, oral supplements are not tolerated for a long period of time, and in most cases with GR and inadequate caloric intake tube feeding is needed. Children learn very quickly to swallow the feeding tube every night without interruption of daily activities.61 Another option is the use of percutaneous gastrostomy (PEG) tubes, and there are reports in children with CD demonstrating the efficacy and safety of using PEG for long-term nutrition support.62, 63

Since remission is a key goal for resumption of adequate growth, it is unknown whether total or partial EN have equivalent effects needed to achieve remission. One recent study addressing this question demonstrated that remission rate with partial EN (50% of daily calories as an elemental diet) was significantly lower than with total EN (100% of calories) given for a 6-week period (15% versus 42%). Furthermore, only total EN lead to a significant decrease in erythrocyte sedimentation rate (ESR).64 In that context, one must bear in mind that EN may be more likely to induce endoscopic and histologic improvement when the ileum is involved.65

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Major loss of body protein mass in inflammatory bowel disease is much less common than weight loss, which is often attributable to losses of other body, particularly water and fat. It does occur, however, in a few patients, especially in those with compromised food intake. It is due principally to the combined effects of diminished intake and excessive intestinal losses of amino nitrogen. Nitrogen metabolism is influenced not only by protein nutritional state and net nitrogen intake but also by disease activity. There is some evidence for abnormally low secretion of growth hormone in adolescents with inflammatory bowel disease and growth failure. Low serum albumin concentrations are not necessarily related to protein undernutrition and are the combined result of relatively reduced albumin synthesis, increased intestinal losses, and maldistribution between intravascular and extravascular spaces. Concentrations in the plasma of IgG and acute phase reactants may be raised despite increased losses into the bowel lumen. The prevention of total body protein depletion is achieved principally by maintaining adequate and often not supranormal intakes of a balanced source of amino nitrogen in a balanced diet given orally, enterally, or parenterally, combined with a medical or surgical approach to reduce disease activity: supranormal energy intakes are not beneficial.

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Caloric and Selected Nutrient Supplementation
The use of enteral/parenteral nutrition as primary ther- apy of active Crohn’s disease is beyond the subject of this review. What follows below is a review of recent data regarding treatment of growth failure, not active disease.
Children with quiescent Crohn’s disease do not have an elevated REE (11). Adaptation downward in REE in CD patients secondary to weight loss appears to be offset by mucosal inflammation (29). Short-and long-term refeeding studies demonstrate significant and sustainable catch-up growth (both height and weight) with aggressive enteral refeeding (29-31). Multiple studies have shown improved height velocity in patients with Crohn’s disease with enteral nutrition, irrespective of whether this was given as nocturnal supplementation, exclusive elemental feeds, or cycling. Many did not comment on pubertal status, and follow-up periods ranged from 6 weeks to 18 months (7,12,32–36).
Therefore,

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Table 1
Accepted Definitions of Growth Failure
• Height below 3rd percentile
• Height velocity less than 3rd percentile for age
• Drop in trajectory of the growth curve >2 major
percentile lines
• Bone age greater than 2 standard deviations below
chronological age
Change in height velocity by pubertal staging
Prepubertal
Females (Tanner 2–3) Males (Tanner 3–4)
4.4 cm/yr 9 cm/yr 10.3 cm/yr

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Approximately 20% of all inflammatory bowel disease (IBD) first presents in childhood or adolescence, and approximately 10% of the estimated 1.4 million Americans with IBD are under age 17. Diagnosis in pediatric patients may be complicated at presentation due to atypical symptoms and/or extraintestinal manifestations (eg, short stature, chronic anemia, unexplained fever, arthritis, mouth ulcers). Pediatric IBD is traditionally diagnosed using endoscopic evaluations of the upper and lower gastrointestinal tract with mucosal biopsies for histologic confirmation. Less invasive serologic testing for IBD may be particularly valuable in pediatric patients, particularly given the association between serum immune reactivity and severe disease phenotypes that is drawing increasing attention. These serologic markers may help stratify risk and identify appropriate pediatric candidates for early aggressive therapy. Serologic testing in pediatric patients includes traditional IBD serologic markers such as anti–Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibody, as well as newer antimicrobial antibodies, including antibodies to outer membrane porin C; I2, a bacterial sequence derived from Pseudomonas fluorescens; and CBir1 flagellin, a colitogenic antigen of the enteric microbial flora in C3H/HeJBir mice strain. Given recent data associating seropositivity with aggressive clinical phenotypes and rapid disease progression, serologic testing may allow early initiation of therapy, maintenance of remission, reduction of corticosteroid exposure, facilitation of mucosal healing, and restoration of normal growth velocity.
Keywords: Inflammatory bowel disease, diagnosis, serologic markers, pediatric, phenotypes, prognostic, biologic therapy

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Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal tract that occur in genetically susceptible individuals. Crohn’s disease (CD) and ulcerative colitis (UC) are two major types of IBD. In about 20–25% of patients, disease onset is during childhood and pediatric IBD can be considered the best model for studying immunopathogentic mechanisms. The fundamentals of IBD pathogenesis are considered a defective innate immunity and bacterial killing with overaggressive adaptive immune response. A condition of “dysbiosis”, with alterations of the gut microbial composition, is regarded as the basis of IBD pathogenesis. The human gastrointestinal (GI) microbial population is a complex, dynamic ecosystem and consists of up to one thousand different bacterial species. In healthy individuals, intestinal microbiota have a symbiotic relationship with the host organism and carry out important metabolic, “barrier,” and immune functions. Microbial dysbiosis in IBD with lack of beneficial bacteria, together with genetic predisposition, is the most relevant conditions in the pathogenesis of the pediatric IBD.

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AuthorsD'Aleo CM, et al. Show all Journal
Pediatr Med Chir. 2009 Jul-Aug;31(4):168-71.
Affiliation
Deparment of Pediatric, Ospedale "M Raimondi", San Cataldo, CL, Italy. [email protected]
Abstract
Inflammatory bowel disease (IBD) include Crohn's disease (CD) and ulcerative colitis (UC). In children signs and symptoms of IBD are often non-specific, diagnosis is more difficult than in adults and systemic manifestation as growth failure and delayed puberty are common. While abdominal pain, rectal bleeding and diarrhoea are usual symptoms, constipation represents an unusual presentation of CD or UC. We report a 9-years-old girl with severe constipation, worsening abdominal pain, intermittent fever, diagnosed as CD. To our knowledge, this is a rare case of CD presenting as chronic constipation in children; we can find, in reviewed recent literature, only few report of similar condition.

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Abstract
Aims: Faecal calprotectin, a neutrophil cytosolic protein, is raised in inflammatory bowel disease. We assessed this investigation in evaluating children with chronic intestinal symptoms. Methods: Stool samples from 100 children aged 5–17 years (referrals to the regional paediatric gastroenterology service) were tested using a commercially available kit. Results: Calprotectin was higher in inflammatory bowel disease than normal children (p<0.0001) or in those with functional constipation (p<0.0001). The overall specificity for organic bowel disorders was 85%. Calprotectin correlated with C-reactive protein in inflammatory bowel disease (p=0.001), and clinical disease activity in ulcerative colitis (p=0.017), but not with disease activity in Crohn's disease.

Conclusion: Raised faecal calprotectin should prompt further assessment in children with chronic intestinal symptoms, since an organic bowel disorder is likely. However, calprotectin cannot be regarded as a specific test for idiopathic inflammatory bowel disease.

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Abstract

Osteoporosis is known to be associated with Crohn’s disease. We report a 12-yr-old boy without a history of steroid use, in whom severe osteoporosis and multiple collapsed vertebrae were the presenting manifestations of Crohn’s disease. After treatment of the Crohn’s disease, he resumed normal growth and progressed through puberty. Concomitantly, he demonstrated a substantial recovery of vertebral bone mineral density and structure. Possible pathophysiological mechanisms underlying the osteoporosis and the subsequent improvement in bone density are discussed.

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my little penguin said:

Childhood Crohn's disease presenting as chronic constipation.

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While abdominal pain, rectal bleeding and diarrhoea are usual symptoms, constipation represents an unusual presentation of CD or UC.

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A 17-year-old boy was admitted to the hospital because of a 6-week history of abdominal pain, constipation, and weight loss. Gastrointestinal radiographs showed narrowing of the cecum. CT scans showed peritoneal implants and a mediastinal mass.

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Women with inflammatory bowel disease (IBD) have similar rates of fertility to the general population, but have an increased rate of adverse pregnancy outcomes compared with the general population, which may be worsened by disease activity. Infertility is increased in those undergoing ileal pouch–anal anastomosis. Anti-tumor necrosis factor therapy in pregnancy is considered to be low risk and compatible with use during conception in men and women and during pregnancy in at least the first two trimesters. Infliximab (IFX) and certolizumab pegol are also compatible with breastfeeding, but safety data for adalimumab (ADA) are awaited. The safety of natalizumab during pregnancy is unknown. For children with Crohn's disease (CD), IFX is effective at inducing and maintaining remission. Episodic therapy is not as effective as scheduled infusions. Disease duration in children does not appear to affect the efficacy of IFX. IFX promotes growth in prepubertal and early pubertal Crohn's patients. It is also effective for the treatment of extraintestinal manifestations. ADA is effective for children with active CD and for maintaining remission, even if they have lost response to IFX, although there are fewer data. Vaccination of infants exposed to biological therapy in utero should be given at standard schedules during the first 6 months of life, except for live-virus vaccines such as rotavirus. Inactivated vaccines may be safely administered to children with IBD, even when immunocompromised.

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DDW: Methotrexate Adds No Benefit to Infliximab (Remicade) in Crohn's Disease
By John Gever, Staff Writer, MedPage Today
Published: May 23, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine
Action Points
Explain to interested patients that the study found no benefit from adding methotrexate to infliximab (Remicade) therapy in Crohn's disease.
Explain that infliximab and methotrexate are each approved individually for Crohn's disease.
Note that this study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
SAN DIEGO, May 23 -- Although both methotrexate and infliximab (Remicade) are known to be effective against Crohn's disease, combining them provides no extra benefit, a researcher said here.


Patients receiving the combination had the same treatment success rate as others treated with infliximab alone in a 50-week, placebo-controlled trial, reported Brian Feagan, M.D., of the Robarts Research Institute in London, Ontario, at Digestive Disease Week.


"Triple induction therapy with methotrexate was not more effective than dual induction therapy followed by infliximab maintenance therapy," he said.


Treatment success was defined by three criteria: score of less than 150 on the Crohn's Disease Activity Index and no clinical need for prednisone supplements at week 14, and no relapse though week 50.


At week 14, 76.2% of patients receiving the combination met the success definition, compared with 77.8% of those taking infliximab and placebo (P=0.83). There were 63 patients in each arm.


Relapse rates were also nearly identical, with 55.6% of combination-treated patients meeting the final success definition at week 50 versus 57.1% of those receiving infliximab and placebo (P=0.86).


Disease duration had no bearing on responses to the combination versus infliximab alone. There were no differences in response rates in patients whose disease onset was less than two years earlier, nor in patients with disease duration of more than 12 years.


Patients in the study were adults with an established Crohn's diagnosis and active symptoms requiring 15 to 40 mg/day of prednisone. Lactating or pregnant women and patients with risk factors for toxicity from the study drugs or recent serious infections were excluded.


Infliximab was given at 5 mg/kg by infusion at weeks one, three, and seven, and every eight weeks thereafter through week 50, with 200 mg of hydrocortisone prior to each infusion. Methotrexate was started at 10 mg weekly by subcutaneous injection, then increased to 25 mg by week seven and continued until week 14. Prednisone was gradually withdrawn over the 14-week induction phase.


Median disease activity scores over the first 14 treatment weeks suggested that the methotrexate-infliximab combination was actually inferior to infliximab alone, although the difference did not reach statistical significance.


Dr. Feagan said that if any advantage for the combination was going to be evident, it would most likely have been in this measure. In fact, the mean score in the combination group at week 14 was about 125, compared with about 100 with infliximab.


Secondary measures of effectiveness, such as scores on the SF-36 health survey instrument, also showed no significant differences between treatments.


There were no major differences in adverse effects in the study, Dr. Feagan said. The most important was that 14 patients in the combination group had disease exacerbations versus four in the infliximab-only group. Infection rates were nearly identical.


Despite the lack of benefit for the combination in the trial, Dr. Feagan said it deserves additional research.


"In my opinion, future studies should concentrate on combination therapy in patients with early disease and in steroid-resistant patients," he said.


Gary Lichtenstein, M.D., of the University of Pennsylvania in Philadelphia, commented that the findings were no surprise.


Earlier studies in his own lab and elsewhere had suggested that combinations of drugs do not add benefit to individual biologic therapies in Crohn's disease, he said.


"In most patients you don't need to add anything. These biologic agents are wonderful drugs by themselves. By adding drugs such as methotrexate or steroids you are just increasing the risk of serious adverse events," he said.


The study was investigator-initiated with support from Schering Canada.

Dr. Feagan reported relationships with Abbott, UCB Pharma, Centocor, Schering-Plough, Novartis, Celgene, Chemocentryx, Procter & Gamble Pharmaceuticals, Otsuka America, Berlex, Santarus, Synta, Genentech, PDL Biopharma, and Elan.


Dr. Lichtenstein reported relationships with Salix, Procter & Gamble, Shire, Axcan, Centocor, UCB, Schering-Plough, Abbott, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Elan, Serono, Wyeth, Millennium, and Protein Design Labs.

Primary source: Digestive Disease Week
Source reference:
Feagan B, "A randomized trial of methotrexate in combination with infliximab for the treatment of Crohn's disease" Digestive Disease

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Quality Improvement in Gastroenterology Clinical Practice
Rakhi Kheraj, Sumeet K. Tewani, Gyanprakash Ketwaroo, Daniel A. Leffler Disclosures
Clin Gastroenterol Hepatol. 2012;10(12):1305-1314.

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Inflammatory Bowel Disease
Bone mineral density (BMD) tests, vaccinations, and dysplasia screens are important components of quality outpatient care for patients with inflammatory bowel disease (IBD).

Osteoporosis and Osteopenia
Patients with IBD are at increased risk for developing osteoporosis and osteopenia; about 15% of patients with IBD also have osteoporosis. [26] Several risk factors for osteoporosis have been identified and include a course of steroid therapy longer than 3 months or recurring use of steroids, age >50 years, postmenopausal status, history of low-impact fracture, and hypogonadism. Using these risk factors to identify patients who should be tested for BMD led to the finding that 69% of patients with IBD were prescribed specific therapy. [27] Currently, the AGA recommends dual-energy x-ray absorptiometry screening for high-risk patients (grade D). [26] However, despite these recommendations and their validation in a prospective cohort, only 23% of patients with risk factors at a representative tertiary institution were tested. [28]

Vaccinations
Although immunosuppressive agents have significantly improved medical management of Crohn's disease and ulcerative colitis, they increase the risk of infection, so vaccinations are important. [29,30] Appropriate routine vaccinations are recommended by the Advisory Committee for Immunization Practices ( Table 1). [31,32] Live vaccines, such as varicella, generate concern among patients with IBD, who are likely to receive immunosuppressive therapy. Consideration of vaccination at initial visit could allow for safe vaccination before initiation of immunosuppressive therapy. Many common vaccines, such as hepatitis A virus, hepatitis B virus (HBV), pneumococcal, injectable influenza, and human papillomavirus, are recommended for individuals on or being considered for immunosuppressive regimens. Despite recommendations, vaccination of patients with IBD is underutilized in general practice. [30]

On the basis of major society guidelines, adequate bone health and infection prevention through appropriate testing and vaccination are considered important parts of outpatient IBD QI. An example of QI initiatives in these areas could include the following steps: (1) development of an evidence-based practice standard for BMD testing and vaccination in patients with IBD; (2) retrospective evaluation of appropriately tested or vaccinated patients; and (3) development or enhancement of a mechanism that increases rates of BMD testing or vaccination in appropriate individuals. Possibilities include patient-completed forms and templated notes in patients' charts to serve as reminders to ordering physicians. Potential initiatives include automated reminder letters for vaccinations, such as influenza, that are needed on a recurring basis. For BMD testing, patients could receive a standardized test referral when they check out from the clinic. QI initiatives should also include (4) a prospective audit of IBD patients to assess rates of appropriate vaccination or referral for BMD testing and (5) evaluations for any potential shortcomings of the system. After this step, healthcare workers should return to step 3.

Screening for Dysplasia
The risk of colorectal cancer and dysplasia is increased in patients with ulcerative and Crohn's colitis, compared with the general population. This risk of colorectal cancer is estimated to be 2% for patients who have had ulcerative colitis for 10 years or more and as high as 18% for those with the disease for 30 years. [33] To reduce the risk of colorectal cancer in patients with IBD, the AGA recommends that all patients undergo surveillance colonoscopy a maximum of 8 years after onset of IBD symptoms [34] (grade B*). Surveillance schedules can then be based on family history, extent and activity of disease, and the presence of primary sclerosing cholangitis or abnormal findings such as polyps and strictures. [19,35,36] The sensitivity of endoscopic screening for dysplasia can be increased by including chromoendoscopy, performance by an experienced endoscopist, and adequate sampling of the colon. [37] When dysplasia or cancer is found, it should be confirmed by a histology analysis by an expert gastrointestinal pathologist. [36,38]

An example of a QI initiative in dysplasia screening would involve the following steps: (1) establish an evidence-based practice guideline for dysplasia screening in patients with longstanding colitis; (2) evaluate the tests performed in a cohort of at-risk IBD patients to identify those who have been screened for dysplasia, have had an adequate number of biopsies analyzed, and those who are undergoing appropriate surveillance; (3) identify patient-based and system-based risk factors for insufficient dysplasia screening and develop a mechanism to improve screening by addressing these risk factors (possible approaches include sending reminder letters, which are generated at initial visit and at each procedure for surveillance colonoscopy and mailed before the suggested appointment); and (4) audit patients who are receiving dysplasia screening under the new quality intervention to evaluate any potential shortcomings and assure that the QI initiative has been modified appropriately.

Medications in Inflammatory Bowel Disease
Infliximab and other anti–tumor necrosis factor-alpha therapies increase the risk of infection and reactivation of tuberculosis (TB) and HBV. [39,40] The ACG therefore recommends routine testing for TB and HBV before anti–tumor necrosis factor therapy begins. [41] Although the rate of screening is increasing, there is a substantial need for QI efforts to improve these rates. [42]

Before patients are treated with 6-mercaptopurine or azathioprine, AGA guidelines recommend thiopurine methyltransferase testing by activity or genotype to identify patients at risk for developing severe bone marrow suppression (grade B). [43] Likewise, it is equally important to monitor patients while they are receiving therapy; systems to ensure appropriate interval laboratory tests and routine follow-up examinations could be included in QI plans.

An example of a QI project to promote the safe use of appropriate medications, such as infliximab, would involve the following steps: (1) an initial retrospective review of patients who are receiving infliximab to ensure documentation of appropriate tests for TB and HBV; (2) implementation of interventions to ensure that patients were tested for these diseases before therapy began (such as a checklist for the ordering physician or the pharmacist to confirm that tests for TB and HBV have been completed before they dispense infliximab); and (3) confirmation of the efficacy of the quality initiative via prospective audit of patients who are receiving infliximab and room for further modification of the initiative to achieve 100% compliance with prescreening for HBV and TB.

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San Diego, October 22, 2012 – Prometheus Laboratories Inc., a specialty pharmaceutical and diagnostic company, will present five abstracts at the American College of Gastroenterology 2012 Scientific Meeting taking place this week in Las Vegas, NV. These data add to the compelling body of evidence that supports standardized use of liquid phase assays in helping to identify potential causes for loss of treatment response among inflammatory bowel disease (IBD) patients using infliximab (IFX).
PROMETHEUS Anser IFX is a proprietary, new generation monitoring test that helps guide patient management decisions – potentially saving IBD patients and their treating physicians valuable time and effort. This liquid phase assay, launched earlier this year, measures drug (infliximab) and drug antibody levels in the presence of drug (infliximab) at anytime in the course of therapy. Prometheus intends to use this platform for subsequent introductions of additional tests targeted to other biologic agents being used to treat a variety of autoimmune diseases.
In one abstract "Comparison of techniques for monitoring infliximab and antibodies to infliximab in Crohn's disease patients with infliximab treatment failure" (Steenholdt et al), the PROMETHEUS Anser IFX diagnostic demonstrated superiority over ELISA, a commonly used solid phase assay for measuring both IFX and antibodies-to-infliximab (ATI) levels. The development of ATIs can shorten the duration of clinical response to IFX and decrease the likelihood of an IBD patient remaining in remission.
In the study, IFX and ATI levels were measured among 67 patients with infliximab treatment failure. PROMETHEUS Anser IFX proved more sensitive than ELISA in detecting absolute trough IFX concentrations (mean difference of 0.60 µg/ml). In addition, ATIs were detectable in only 6 (9%) of ELISA patients, as compared to 23 (35%) of the PROMETHEUS Anser IFX patients. Of the 17 samples for which ATI were detected by PROMETHEUS Anser IFX and missed by ELISA, 14 had detectable IFX levels that were likely missed due to interference from serum IFX, a common shortcoming of the solid phase ELISA assay and further support for the use of the new liquid test.

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This guideline is subdivided into selected medication options, such that the following will be addressed:
• recommended care prior to treatment
• induction and maintenance with the following
medications
• 6-mercaptopurine (6-MP) or azathioprine (AZA)
(Imuran®/Azasan®) with or without prednisone
OR
• methotrexate (MTX) OR
• infliximab (Remicade®)
• other treatment related interventions
• patient / family education.
Target Population
Children 0 to 22 years of age diagnosed with Inflammatory Bowel Disease (IBD) [either Crohn’s Disease (CD) or Ulcerative Colitis (UC)].
Target Users
Include but are not limited to (in alphabetical order):
• clinicians caring for patients diagnosed with IBD
• patient care staff, including:
• nurse practitioners
• nurses
• patients and families
• physicians in training
• primary care providers

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Corticosteroids can be administered as oral (cortisone, prednisone, prednisolone, budesonide), intravenous (prednisolone, methylprednisolone, corticotropin), or rectal (beclomethasone, tixicortol, budesonide, prednisolone metasulfobenzoate) formulations. Truelove and Witts reported the efficacy of cortisone 100 mg per day in UC in 1955.8 Baron and colleagues then reported that 40 mg of prednisone was more effective than 20 mg and equally effective as 60 mg, but with fewer side effects.50 Finally, single daily dosing of prednisone 40 mg daily was equally effective as 10 mg four times a day.51 It is from these early studies that the current maxim of prednisone 40 mg per day for moderate to severe UC originated. No maintenance benefit of corticosteroids in UC has been found.52

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780076/#r17007-8

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my little penguin said:

http://www.cincinnatichildrens.org/WorkArea/DownloadAsset.aspx?id=87937


Evidence-Based Care Guideline
Management of Pediatric
Moderate / Severe Inflammatory
Bowel Disease (IBD):

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Infliximab (Remicade®; Schering-Plough, Kenilworth, NJ, U.S.A.) is a chimeric monoclonal antibody (75% human, 25% mouse) that acts as a tumour necrosis factor-α inhibitor. Infliximab is registered for treatment of rheumatoid arthritis (RA), psoriatic arthritis, Crohn disease, ulcerative colitis, ankylosing spondylitis and plaque-type psoriasis. In dermatology it is also used for off-label indications such as hidradenitis suppurativa and pyoderma gangrenosum among others.[1] Infliximab has proven to be very effective in the treatment of moderate to severe chronic plaque-type psoriasis. In several randomized controlled trials (RCTs) around 80% of patients showed an improvement of at least 75% in the Psoriasis Area and Severity Index (PASI 75) after 10weeks of treatment, and more than half of the patients even showed an improvement of more than 90% (PASI 90).[2-4]

During and after the intravenous administration of infliximab infusion reactions can occur, comparable with what happens when using other foreign protein-derived treatments. Infusion reactions during the infusion or in the first 24h afterwards are defined as acute reactions.[5,6] The majority occurs during or in the first 2h after the infusion. Symptoms include 'flushing', chest tightness, dizziness, shortness of breath, headache, hypo/hypertension, nausea, sweating, rise in temperature and (other) symptoms of anaphylaxis, like urticaria and bronchospasms.[3,5,7] Delayed reactions are reactions that occur between 24h and 14days after an infusion, the majority occurring after 5-7days.[5] In most cases symptoms include arthralgia, myalgia, influenza-like symptoms, headache, tiredness and 'rash' or urticaria.[4,5,8]

Infusion reactions appear in 3-22% of patients with psoriasis who are treated with infliximab;[7] in placebo arms this is approximately 0-2%.[3,4] The reactions can be subdivided into mild, moderate or severe reactions. Most reactions are mild or moderate and only few are severe.[3] The severity of infusion reactions is assigned by the physician based on the patient's signs and symptoms; however, they do not always fit neatly into the definition of mild, moderate or severe reactions.[6] Mild reactions can be defined as reactions that are self-limiting and resolve spontaneously after temporary cessation of the infusion or reduction of the infusion speed. Moderate reactions are those that require closer attention and an extended observation period and often discontinuation of the infusion. Serious reactions involve respiratory symptoms or a symptomatic blood pressure drop and need for close monitoring, often for 24h and occasionally requiring hospital admission.[9] A severe infusion reaction can be anaphylactic or anaphylactoid and should be treated as such (Fig. 1). In these cases infliximab should be stopped immediately.[5]

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Abstract

Purpose of review To highlight the advances in MRI of the small intestine in patients with Crohn's disease. MRI of the gut has become more feasible with improved spatial resolution and speed of the MR sequences allowing parallel evaluation for both disease activity and extra-enteric complications.

Recent findings Recent literature highlights excellent diagnostic accuracy of MR enterography (MRE) that is comparable to computed tomography enterography (CTE). Compared to CTE the image quality is not quite as good, and there is slightly more interobserver variability in interpretation. Despite these performance characteristics, the overall diagnostic yield of MRE is comparable to CTE. The lack of radiation exposure related to MRE is a significant strength, especially in Crohn's population that by virtue of their younger age, body habitus and potential need for repeated imaging, is at highest risk of potential cancer from radiation exposure due to diagnostic imaging. MRE should not be viewed as a 'safer' version of a CTE. The physics of MRI allows the application of unique sequences that add novel insights not possible with other imaging modalities.

Summary MRE is a highly effective technique for assessing Crohn's disease. We are only starting to explore new MRI sequences and the future of this technology is extremely exciting.

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Tesscorm said:

Thought this was a great link that vtfamily posted.

Clinical Imaging of the Small Intestine

http://books.google.com/books?id=sOr...0bowel&f=false

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Go to:
Abstract
Background and aims
Total enteral nutrition (TEN) with a liquid formula can suppress gut inflammation and induce remission in active Crohn's disease. The mechanism is obscure. Studies have suggested that long term nutritional supplementation with a liquid formula (partial enteral nutrition (PEN)) may also suppress inflammation and prevent relapse. The aim of this study was to compare PEN with conventional TEN in active Crohn's disease.
Patients and methods
Fifty children with a paediatric Crohn's disease activity index (PCDAI) >20 were randomly assigned to receive 50% (PEN) or 100% (TEN) of their energy requirement as elemental formula for six weeks. The PEN group was encouraged to eat an unrestricted diet while those receiving TEN were not allowed to eat. The primary outcome was achievement of remission (PCDAI <10). Secondary analyses of changes in erythrocyte sedimentation rate (ESR), C reactive protein, albumin, and platelets were performed to look for evidence of anti‐inflammatory effects.
Results
remission rate with PEN was lower than with TEN (15% v 42%; p=0.035). Although PCDAI fell in both groups (p=0.001 for both), the reduction was greater with TEN (p=0.005). Moreover, the fall in PCDAI with PEN was due to symptomatic and nutritional benefits. With both treatments there were significant improvements in relation to abdominal pain, “sense of wellbeing”, and nutritional status. However, only TEN led to a reduction in diarrhoea (p=0.02), an increase in haemoglobin and albumin, and a fall in platelets and ESR.
Conclusions
TEN suppresses inflammation in active Crohn's disease but PEN does not. This suggests that long term nutritional supplementation, although beneficial to some patients, is unlikely to suppress inflammation and so prevent disease relapse.
Keywords: Crohn's disease, enteral nutrition, elemental diet, children

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Clinical Imaging of the Small Intestine

http://books.google.com/books?id=sOr...0bowel&f=false
This link didn't work for me.

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OBJECTIVES: The use of tumor necrosis factor-alpha (TNF-) antagonists has changed the therapeutic strategy for Crohn's disease (CD). Adalimumab (ADA), a fully human anti-TNF- monoclonal antibody, is an effective therapy for patients with CD, both naive patients and those intolerant or refractory to Infliximab (IFX), a chimeric anti-TNF- agent. However, the use of ADA is rarely reported in pediatric CD. We performed an open prospective evaluation of short- and long-term efficacy and safety of ADA in children with moderate-to-severe CD.
METHODS: A total of 23 pediatric CD patients (9 naive and 14 intolerant or unresponsive to IFX) received ADA subcutaneously as a loading schedule at weeks 0 and 2, and at every other week (eow) during a 48-week maintenance phase. Loading and maintenance doses were 160/80 and 80 mg eow in 13 cases, 120/80 and 80 mg eow in 2, and 80/40 and 40 mg eow in 8 cases. The primary efficacy outcomes were clinical remission and response at different scheduled visits along the maintenance phase. At baseline, 13 patients also received immunomodulators (IMs).
RESULTS: At weeks 2, 4, 12, 24, and 48, remission rates were 36.3, 60.8, 30.5, 50, and 65.2%, respectively, whereas response rates were 87, 88, 70, 86, and 91%, respectively. Four patients at week 24 and 2 at week 48 received IMs; the mean daily corticosteroid dose, disease activity index, C-reactive protein level, and erythrocyte sedimentation rate decreased significantly throughout the trial. No serious adverse events were recorded.
CONCLUSIONS: ADA can be an effective and safe biological agent for inducing and maintaining remission in children with moderate-to-severe CD, even in those with previous IFX therapy.

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While surgical resection remains a mainstay of the treatment of Crohn’s disease (CD),
postoperative recurrence of disease is common. The ideal management of patients after
surgery is unclear and varies widely in clinical practice. Both patients and clinicians
must weigh the risks and benefits of treatment in reaching a decision. Those at low risk
of postoperative recurrence may not need any therapy while those at moderate risk of
disease recurrence may be treated with immunomodulator therapy. Patients with the
highest risk for recurrence should ideally be treated with biologic therapy. Regardless
of risk, all patients should undergo ileocolonoscopic surveillance at 6–12 months after
surgery. This review will outline the current evidence for various medical therapies in
the prevention of postsurgical recurrence and outline a management algorithm of these
patients based on risk stratification.

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During a heat wave, there is more to worry about than just heat stroke: Flares of inflammatory bowel disease (IBD) and bouts of infectious gastroenteritis (IG) are things to consider as well, according to a study from Zurich, Switzerland, published online August 13 in the American Journal of Gastroenterology.

"There is evidence for an increase of IBD hospital admissions by 4-6 percent for each additional day within a heat wave period," Christine N. Manser, MD, from the Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital, Zurich, and colleagues said in a new release. "Presence of a heat wave was estimated to increase the risk of [IG] by 4-7 percent for every additional day within a heat [wave] period. In the control group there was no evidence for a heat wave effect."

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RESULTS: At the time of diagnosis in children, CD involved small bowel and colon (L3) in 51% (138/273), colon (L2) in 36%, and ileum (L1) in 6%; the upper gastrointestinal (GI) tract (L4) was also affected in 51%. In 39%, the anatomic extent increased within 2 years. Behavioral characteristics progressed; 24% of children developed stricturing or penetrating complications within 4 years (vs 9% at diagnosis; P < .0001; odds ratio [OR], 3.32; 95% confidence interval [CI], 1.86-5.92). Compared with adults, childhood-onset disease was characterized by a "panenteric" phenotype (ileocolonic plus upper GI [L3+L4]; 43% vs 3%; P < .0001; OR, 23.36; 95% CI, 13.45-40.59) with less isolated ileal (L1; 2% vs 31%; P < .0001; OR, 0.06; 95% CI, 0.03-0.12) or colonic disease (L2; 15% vs 36%; P < .0001; OR, 0.31; 95% CI, 0.21-0.46). UC was extensive in 82% of the children at diagnosis, versus 48% of adults (P < .0001; OR, 5.08; 95% CI, 2.73-9.45); 46% of the children progressed to develop extensive colitis during follow-up. Forty-six percent of children with CD and 35% with UC required immunomodulatory therapy within 12 months of diagnosis. The median time to first surgery was longer in childhood-onset than adult-onset patients with CD (13.7 vs 7.8 years; P < .001); the reverse was true for UC.

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Tesscorm said:

Anatomy and Histology of the Small and Large Intestine

http://jpck.zju.edu.cn/jcyxjp/files/ge/05/MT/0511.pdf

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Tesscorm said:

View attachment 2105

Not sure why link didn't work... can you read this file?

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ABSTRACT AND INTRODUCTION
Abstract

Objectives: Several anti-tumor necrosis factor-α (TNFα) antibodies have demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC). These drugs carry the theoretical risk of opportunistic infection, but no systematic review and meta-analysis has examined this issue specifically.

Methods: MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through to November 2012). Randomized controlled trials (RCTs) recruiting adults with active or quiescent CD or UC comparing anti-TNFα therapy with placebo were eligible. Dichotomous data were pooled to obtain a relative risk (RR) of opportunistic infection, with a 95% confidence interval (CI). The number needed to harm (NNH) was estimated from the reciprocal of the risk difference from the meta-analysis.

Results: The search strategy identified 20,563 citations, 21 of which were eligible, reporting 22 separate RCTs with between 2 and 56 weeks of follow-up. In total, there were 39 (0.9%) opportunistic infections among 4,135 patients allocated to anti-TNFα therapy, compared with 9 (0.3%) among 2,919 assigned to placebo. Among patients receiving active therapy these included eight cases of Mycobacterium tuberculosis, eight cases of herpes simplex infection, six cases of oral or esophageal candidiasis, six cases of herpes zoster infection, two cases of varicella-zoster virus infection, two cases of cytomegalovirus or Epstein–Barr virus infection, and one case of Nocardia infection. The RR of developing an opportunistic infection was significantly higher with anti-TNFα therapy (2.05; 95% CI 1.10–3.85, NNH=500; 95% CI 200–1,567). The RR of tuberculosis infection was 2.52 (95% CI 0.62–10.21).

Conclusions: Anti-TNF therapy doubles the risk of opportunistic infections in inflammatory bowel disease patients. This underlines the importance of adherence to guidelines for their prevention and management.

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Anti-tumour necrosis factor-α antibodies are useful for the treatment of refractory Crohn's disease and ulcerative colitis. Thalidomide is another agent with tumour necrosis factor-α suppressive properties.

Aim
To investigate the long-term efficacy and safety of thalidomide in a group of children and young adults with refractory inflammatory bowel disease.

Methods
Twenty-eight patients with refractory moderate-severe inflammatory bowel disease (19 Crohn's disease, 9 ulcerative colitis) received thalidomide 1.5–2.5 mg/kg/day. Patients were assessed at baseline, at weeks 2, 4, 8 and 12, and then every 12 weeks by patient's diary, physical examinations, laboratory analyses and scoring on activity indexes. Primary outcomes were: (i) efficacy in inducing remission; and (ii) efficacy in maintaining remission.

Results
remission was achieved with thalidomide in 21 of 28 (75%) patients (17 with Crohn's disease, 4 with ulcerative colitis). Mean duration of remission was 34.5 months. Sixteen of 20 (80%) patients suspended steroids. Reversible neuropathy occurred in seven of 28 (25%) patients, but only with cumulative doses over 28 g. Other side effects requiring thalidomide suspension were vertigo/somnolence (one of 28), and agitation/hallucinations (one of 28).

Conclusions
Thalidomide seems to be effective in inducing long-term remission in children and adolescents with intractable inflammatory bowel disease. Neuropathy is the main adverse effect, but appears to be cumulative dose-dependent, thus allowing long-term remission before drug suspension.

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