Methotrexate for Inflammatory Bowel Diseases - New Developments

Methotrexate (MTX) is an established therapy for patients with steroid dependent Crohn’s disease (CD). MTX is also frequently used in combination with anti-TNF agents to suppress anti-drug antibody formation. It has been suggested in the past that MTX lacks any clinical effectiveness in patients with ulcerative colitis (UC), however newer data at least partially contradict this assumption. The following review will discuss recent data for the use of MTX in CD, UC and in combination with anti-TNF agents

Imaging in Inflammatory Bowel Diseases - Magnetic Resonance Imaging

Diagnostic imaging techniques play an important role in the diagnosis and management of patients with inflammatory bowel diseases (IBDs). The approach should be guided by considerations of diagnostic accuracy, concerns about patient exposure to ionizing radiation, local expertise and tolerance of the endoscopic and/or imaging technique. In regard to the clinical diagnostic value (sensitivity, specificity and accuracy), no significant differences exist between CT and MRI for the evaluation of the extent of inflammation, stricturing, penetrating disease or extraluminal complications such as abscesses. Due to the absence of radiation exposure, MRI of the intestine is recommended as the first-line imaging modality in patients with suspected or established IBD. The focus of this review is the latest developments in MRI techniques to detect IBDs. Specifically, the use of new indices for the grading of inflammation or assessing bowel damage as well as innovative experimental approaches such as diffusion-weighted imaging or magnetization-transfer MRI to evaluate and quantify the degree of intestinal inflammation and fibrosis in stricturing Crohn's disease are discussed

Cytomegalovirus viral load in the colon and risk of colectomy in hospitalized patients with inflammatory bowel diseases

To the Editor: We read with interest the article of Lee et al1 describing the risk factors for adverse outcomes in hospitalized patients with ulcerative colitis (UC) with concurrent cytomegalovirus (CMV) colitis. CMV reactivation and resolution can be spontaneous in patients with UC regardless of antiviral therapy; however, inconsistencies between CMV detection methods of various studies and criteria for defining CMV positivity may be leading to these disparate findings.2,3 In the study by Lee et al, CMV colitis was defined by the presence of 1 or more inclusion bodies on hematoxylin and eosin staining or CMV immunohistochemistry on colonic biopsies. The most accurate approach for detection of clinically significant CMV infection has not been firmly established and guidelines differ in their recommendations.3,4 A recent study using quantitative colonic PCR in consecutive patients with UC undergoing endoscopy in the setting of a moderate to severe flare demonstrated a correlation between higher viral load and resistance to immunosuppressive therapy with significant differences found when using a cutoff viral load of .250 per milligram tissue.

American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases

Therapeutic drug monitoring (TDM), which involves measurement of drug or active metabolite levels and anti-drug antibodies, is a promising strategy that can be used to optimize inflammatory bowel disease therapeutics. It is based on the premise that there is a relationship between drug exposure and outcomes, and that considerable inter-individual variability exists in how patients metabolize the drug (pharmacokinetics) and the magnitude and duration of response to therapy (pharmacodynamics). Therefore, the American Gastroenterological Association has prioritized clinical guidelines on the role of TDM in the management of inflammatory bowel disease. To inform these clinical guidelines, this technical review was developed in accordance with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework for interventional and prognostic studies, and focused on the application of TDM for biologic therapy, specifically anti-tumor necrosis factor-α agents, and for thiopurines. Focused questions address the benefits and risks of a strategy of reactive TDM (in patients with active inflammatory bowel disease) to guide treatment changes compared with empiric treatment changes, and the benefits and risks of a strategy of routine proactive TDM (during routine clinical care in patients with quiescent disease) compared with no routine TDM. Additionally, the review addresses the benefits and risks of routine measurement of thiopurine methyltransferase enzyme activity or genotype before starting thiopurine therapy compared with empiric weight-based dosing and explores the performance of different trough drug concentrations for anti-tumor necrosis factor agents and thiopurines to inform clinical decision making when applying TDM in a reactive setting. Due to a paucity of data, this review does not address the role of TDM for more recently approved biologic agents, such as vedolizumab or ustekinumab

Frequency and significance of the novel single nucleotide missense polymorphism Val109Asp in the human gene encoding omentin in Caucasian patients with type 2 diabetes mellitus or chronic inflammatory bowel diseases

BACKGROUND: The omental adipose tissue is pathogenetically involved in both type 2 diabetes mellitus (T2D) and chronic inflammatory bowel diseases (IBD) such as Ulcerative colitis (UC) and Crohn's Disease (CD). Thus, adipokines secreted from omental adipose tissue might play an important role in these diseases. Omentin represents a new adipokine expressed in and secreted by omental adipose tissue. Therefore, it was the aim to investigate the putative role of a newly described sequence missense variation in the human omentin gene. METHODS: The Val109Asp single nucleotide miss-sense polymorphism and the His86His polymorphism in exon-4 of the omentin gene were newly identified by random sequencing. Only the miss-sense polymorphism was investigated further. Genotyping was performed by restriction fragment length polymorphism (RFLP) analysis of amplified DNA fragments. Three different cohorts of well-characterized individuals were included in the study. 114 patients suffering from T2D, 190 patients suffering from IBD (128 with CD and 62 with UC) and 276 non-diabetic healthy controls without any history for IBD were analyzed. RESULTS: The following allelic frequencies were determined: controls: Val-allele: 0.26, Asp-allele: 0.74; T2D: Val-allele: 0.3, Asp-allele: 0.7; IBD: Val-allel: 0.31, Asp-allele: 0.69. UC and CD patients did not differ in regard to the allelic frequency. Similarly, controls, T2D patients and IBD patients did not show significant differences in genotype distribution among each other. Disease manifestation and pattern of infestation were not related to genotype subgroups, neither in CD nor in UC. Furthermore, there was no significant association between genotype subgroups and anthropometric or laboratory parameters in T2D patients. CONCLUSION: Based on sequence comparisons and homology searches, the amino acid position 109 is conserved in the omentin gene of humans, mice and chimpanzee but is not completely conserved between other omentin homologous genes. Moreover, position 109 lies outside the fibrinogen domain. Due to these structural features and based on the present data, the Val109Asp sequence variation is more a single nucleotide polymorphism than a real disease-causing mutation

Prevalence of a Gluten-free Diet and Improvement of Clinical Symptoms in Patients with Inflammatory Bowel Diseases:

Background—Maintaining a gluten free diet (GFD) without an underlying diagnosis of celiac disease has enjoyed widespread acceptance in the USA. Methods—We performed a cross-sectional study utilizing a GFD questionnaire in 1647 patients with inflammatory bowel diseases (IBD) participating in the CCFA Partners longitudinal, Internet-based cohort. Results—A diagnosis of celiac disease (CD) and non-celiac gluten sensitivity (NCGS) were reported by 10 (0.6%) and 81 (4.9%) respondents, respectively. Three hundred fourteen (19.1%) participants reported having previously tried a GFD and 135 (8.2%) reported current use of GFD. Overall 65.6% of all patients, who attempted a GFD described an improvement of their GI-symptoms and 38.3% reported fewer or less severe IBD flares. In patients currently attempting a GFD, excellent adherence was associated with significant improvement of fatigue (p<0.03). Conclusion—In this large group of patients with IBD, a substantial number had attempted a GFD, of whom the majority had some form of improvement in GI-symptoms. Testing a GFD in clinical practice in patients with significant intestinal symptoms, which are not solely explained by the degree of intestinal inflammation, has the potential to be a safe and highly efficient therapeutic approach. Further prospective studies into mechanisms of gluten sensitivity in IBD are warranted

Methotrexate: Underused and Ignored?

For greater than a decade, methotrexate has been known to be an effective therapeutic agent in the treatment of steroid dependent active Crohn's disease. However, international data on medication utilization suggest that this drug is rarely used in clinical practice for an indication of Crohn's disease. This review investigates the potential reasons for the underuse of methotrexate in patients with inflammatory bowel diseases

Use of Biologics in Pouchitis: A Systematic Review

Data about the effectiveness of biologics, including anti-TNF therapy and anti-integrin strategies, in antibiotic refractory pouchitis or Crohn’s disease-associated pouch complications are sparse. We performed a systematic review of the literature in Medline and Web of Science. All English language publications and meeting abstracts describing patients with pouchitis treated with anti-TNF or anti-integrin therapies were included. We identified a total of 17 papers and 2 abstracts, most of these retrospective case series, including a total of 192 patients treated either with infliximab (IFX; n=140) or adalimumab (ADA; n=52). No reports were found for anti-integrin therapies or other anti-TNF agents such as certolizumab pegol or golimumab. Due to the heterogeneity of the studies, small numbers of patients, differing co-treatments and subjective outcome definitions, the exact efficacy of these biologic therapies cannot be assessed in a combined fashion. Overall IFX appears to have good clinical effectiveness in selected patients achieving up to 80% short and around 50% long-term response, whereas the few data available for ADA are not sufficient to draw valid conclusions. Larger prospectively collected multi-center data with clearly defined inclusion criteria and outcomes are necessary to better define the clinical value of anti-TNF therapy in patients with antibiotic refractory pouchitis or Crohn’s-like complications of the pouch

Modulation of the Intestinal Microbiota Alters Colitis-Associated Colorectal Cancer Susceptibility

It is well established that the intestinal microbiota plays a key role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) collectively referred to as inflammatory bowel disease (IBD). Epidemiological studies have provided strong evidence that IBD patients bear increased risk for the development of colorectal cancer (CRC). However, the impact of the microbiota on the development of colitis-associated cancer (CAC) remains largely unknown. In this study, we established a new model of CAC using azoxymethane (AOM)-exposed, conventionalized-Il10−/− mice and have explored the contribution of the host intestinal microbiota and MyD88 signaling to the development of CAC. We show that 8/13 (62%) of AOM-Il10−/− mice developed colon tumors compared to only 3/15 (20%) of AOM- wild-type (WT) mice. Conventionalized AOM-Il10−/− mice developed spontaneous colitis and colorectal carcinomas while AOM-WT mice were colitis-free and developed only rare adenomas. Importantly, tumor multiplicity directly correlated with the presence of colitis. Il10−/− mice mono-associated with the mildly colitogenic bacterium Bacteroides vulgatus displayed significantly reduced colitis and colorectal tumor multiplicity compared to Il10−/− mice. Germ-free AOM-treated Il10−/− mice showed normal colon histology and were devoid of tumors. Il10−/−; Myd88−/− mice treated with AOM displayed reduced expression of Il12p40 and Tnfα mRNA and showed no signs of tumor development. We present the first direct demonstration that manipulation of the intestinal microbiota alters the development of CAC. The TLR/MyD88 pathway is essential for microbiota-induced development of CAC. Unlike findings obtained using the AOM/DSS model, we demonstrate that the severity of chronic colitis directly correlates to colorectal tumor development and that bacterial-induced inflammation drives progression from adenoma to invasive carcinoma