Associations Between Obesity and the Effectiveness of Anti-Tumor Necrosis Factor-α Agents in Inflammatory Bowel Disease Patients: A Literature Review and Meta-analysis.

Background: A total of 15% to 40% of adult inflammatory bowel disease (IBD) patients are obese. The influence of obesity on anti-tumor necrosis factor-α (anti-TNF-α) treatment in IBD patients is not consistent. Objective: To determine the association between obesity and the efficacy of anti-TNF treatment in IBD patients. Methods: We performed a systematic search from January 1990 through November 2019 on MEDLINE, Web of Science, Google Scholar, ClinicalTrials.gov, and Cochrane library. We included randomized controlled trials and observational cohort studies that investigated the outcome of anti-TNF treatment in IBD patients with stratification according to body mass index or body weight. The odds ratio (OR) and its 95% CI were calculated. Results: In this pooled meta-analysis, we observed that obesity increased the odds of failure of anti-TNF therapy (OR = 1.195; 95% CI = 1.034-1.380; P = 0.015; I2 = 47.8%). After performing subgroup analyses, obesity was associated with higher odds of anti-TNF treatment failure in ulcerative colitis (UC) patients (OR = 1.413; 95% CI = 1.008-1.980; P = 0.045; I2 = 20.0%) but not in Crohn's disease patients (OR = 1.099; 95% CI = 0.928-1.300). Obesity significantly increased the odds of treatment failure of both dose-fixed and weight-based anti-TNF agents (OR = 1.121, 95% CI = 1.027-1.224, P = 0.011, and OR = 1.449, 95% CI = 1.006-2.087, P = 0.046, respectively). Conclusion and Relevance: In our meta-analysis, obesity was associated with the inferior response of anti-TNF treatments in UC patients. Clinicians should be aware that obese UC patients may require higher doses in anti-TNF treatment.

Natural killer T cells and ulcerative colitis.

Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease (IBD). Both innate immunity and adaptive immunity are aberrant in IBD. The pathogenesis of UC includes abnormal inflammation and immune responses of the digestive tract. Natural killer T (NKT) cells participate in the innate and adaptive immune responses, together with a vast array of cytokines. Recent studies suggested that IL-13, IL5 and IL-4 are involved in the occurrence and the development of UC. Manipulating NKT cells may be a potential strategy to reconstruct the abnormal immune responses in UC. In this review, we explore the roles of NKT cells and cytokines in UC. Additionally, neutralizing antibodies and inhibitors of cytokines produced by NKT cells or their receptors are also discussed as novel therapeutic choices for UC.

Microscopic features of small bowel mucosa of patients with Crohn's disease.

BACKGROUND: Double-balloon enteroscopy enables performing numerous small bowel biopsies for pathologic analysis. However, most histopathological characteristics of Crohn's disease are non-specific characteristics. We aimed to explore the small bowel mucosal histopathologic characters of Crohn's disease and identify some disease-specific changes. METHODS: We included 253 patients without tumors and grouped them into Crohn's disease, suspected Crohn's disease, and non-Crohn's disease groups. These patients underwent double-balloon endoscopy examination and small bowel biopsy at Renji Hospital, Shanghai. All histopathological sections were reviewed, and > 20 histopathological parameters were assessed. Immunohistochemistry was conducted when necessary. RESULTS: There were different forms of granulomatous lymphangitis on the small bowel mucosa in Crohn's disease. They showed as various macrophages or epithelioid cells in the lumina of lymphatics or in the center of the villi with or without evident obstruction. These features were only observed in Crohn's disease patients. Furthermore, they were correlated with granuloma and lymphangiectasia. Additionally, 15 other features showed significant differences among the three groups, and Crohn's disease patients showed an average of almost seven histopathological characteristics. CONCLUSIONS: We described the detailed morphologies of granulomatous lymphangitis on the small bowel mucosa and recommend it as a useful histopathological feature for the diagnosis of Crohn's disease. In terms of specificity and sensitivity, it was superior to non-caseating epithelioid granuloma.

Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia.

The Asia-Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, under the auspices of the Asia-Pacific Association of Gastroenterology with the goal of improving inflammatory bowel disease care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn's and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in conjunction with conventional treatments for ulcerative colitis and Crohn's disease in Asia. These statements also address how pharmacogenetics influences the treatments of ulcerative colitis and Crohn's disease and provides guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of inflammatory bowel disease workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing, and future revisions are likely as new data continue to emerge.

Crosstalk between intestinal epithelial cell and adaptive immune cell in intestinal mucosal immunity.

Constantly challenged by luminal bacteria, intestinal epithelium forms both a physical and biochemical defense against pathogens. Besides, intestinal epithelium senses dynamic and continuous changes in luminal environment and transmits signals to subjacent immune cells accordingly. It has been long accepted that adaptive immune cells fulfill their roles partly by modulating function of intestinal epithelial cells. Recent studies have brought up the proposal that intestinal epithelial cells also actively participate in the regulation of adaptive immunity, especially CD4+ adaptive T cells, which indicates that there is reciprocal crosstalk between intestinal epithelial cells and adaptive immune cells, and the crosstalk may play important role in intestinal mucosal immunity. This Review makes a comprehensive summary about crosstalk between intestinal epithelial cells and CD4+ adaptive T cells in intestinal immunity. Special attention would be given to their implications in inflammatory bowel disease pathogenesis and potential therapeutic targets.

Exosome in intestinal mucosal immunity.

Intercellular communication of immune cells is critical to elicit efficient inflammatory responses. In intestinal mucosa, imbalance in pro-inflammatory and anti-inflammatory mediators, especially cytokines and chemokines, characterizes the underlying immune mechanisms of inflammatory bowel disease. Exosomes, small membrane vesicles secreted into the extracellular environment, are emerging as another important intercellular messenger in immune responses. A major recent breakthrough in this field unveils the capacity of exosomes to mediate the functional transfer of genetic materials (mRNAs and miRNAs) between immune cells. RAB27A and RAB27B are two small GTPases involved in exosome secretion. With respect to intestinal mucosal immunity, increased number of RAB27A-positive immune cells and RAB27B-positive immune cells are demonstrated in the colonic mucosa of patients with active ulcerative colitis as compared with that of healthy controls. This indicates the important role of exosome-mediated immune responses in the pathogenesis of inflammatory bowel disease. Here, we will discuss the immune properties of exosomes and recent advances in their function with a special focus on intestinal mucosal immunity.

Seasonal variation in onset and relapse of IBD and a model to predict the frequency of onset, relapse, and severity of IBD based on artificial neural network.

BACKGROUND: Previous research has yielded conflicting data as to whether the natural history of inflammatory bowel disease follows a seasonal pattern. The purpose of this study was (1) to determine whether the frequency of onset and relapse of inflammatory bowel disease follows a seasonal pattern and (2) to establish a model to predict the frequency of onset, relapse, and severity of inflammatory bowel disease (IBD) with meteorological data based on artificial neural network (ANN). METHOD: Patients with diagnosis of ulcerative colitis (UC) or Crohn's disease (CD) between 2003 and 2011 were investigated according to the occurrence of onset and flares of symptoms. The expected onset or relapse was calculated on a monthly basis over the study period. For artificial neural network (ANN), patients from 2003 to 2010 were assigned as training cohort and patients in 2011 were assigned as validation cohort. Mean square error (MSE) and mean absolute percentage error (MAPE) were used to evaluate the predictive accuracy. RESULTS: We found no seasonal pattern of onset (P = 0.248) and relapse (P = 0.394) among UC patients. But, the onset (P = 0.015) and relapse (P = 0.004) of CD were associated with seasonal pattern, with a peak in July and August. ANN had average accuracy to predict the frequency of onset (MSE = 0.076, MAPE = 37.58%) and severity of IBD (MSE = 0.065, MAPE = 42.15%) but high accuracy in predicting the frequency of relapse of IBD (MSE = 0.009, MAPE = 17.1%). CONCLUSION: The frequency of onset and relapse in IBD showed seasonality only in CD, with a peak in July and August, but not in UC. ANN may have its value in predicting the frequency of relapse among patients with IBD.

CNTNAP3 associated ATG16L1 expression and Crohn's disease.

Autophagy is a common physiological process in cell homeostasis and regulation. Autophagy-related gene mutations and autophagy disorders are important in Crohn's disease (CD). The nucleotide oligomerization domain 2-autophagy genes autophagy 16-like 1 (NOD2-ATG16L1) signaling axis disorder contributes to the dysfunction of autophagy. This paper is focused on the relationship between contactin associated protein-like 3 (CNTNAP3) and ATG16L1 expression in Crohn's disease. The results indicated that the expression of ATG16L1 is higher in some CD patients compared to normal controls. ATG16L1 was well correlated with the C-reactive protein (CRP) in some CD patients. In vitro study revealed that CNTNAP3 could upregulate the expression of ATG16L1 and increase autophagy vacuoles.

Using cognitive theory to facilitate medical education.

BACKGROUND: Educators continue to search for better strategies for medical education. Although the unifying theme of reforms was "increasing interest in, attention to, and understanding of the knowledge base structures", it is difficult to achieve all these aspects via a single type of instruction. METHODS: We used related key words to search in Google Scholar and Pubmed. Related search results on this topic were selected for discussion. RESULTS: Despite the range of different methods used in medical education, students are still required to memorize much of what they are taught, especially for the basic sciences. Subjects like anatomy and pathology carry a high intrinsic cognitive load mainly because of the large volume of information that must be retained. For these subjects, decreasing cognitive load is not feasible and memorizing appears to be the only strategy, yet the cognitive load makes learning a challenge for many students. Cognitive load is further increased when inappropriate use of educational methods occurs, e.g., in problem based learning which demands clinical reasoning, a high level and complex cognitive skill. It is widely known that experts are more skilled at clinical reasoning than novices because of their accumulated experiences. These experiences are based on the formation of cognitive schemata. In this paper we describe the use of cognitive schemata, developed by experts as worked examples to facilitate medical students' learning and to promote their clinical reasoning. CONCLUSION: We suggest that cognitive load theory can provide a useful framework for understanding the challenges and successes associated with education of medical professionals.

LncRNA DQ786243 affects Treg related CREB and Foxp3 expression in Crohn's disease.

BACKGROUND: Long non-coding RNAs (lncRNAs) have different functions in cells. They work as signals, decoys, guides, and scaffolds. Altered lncRNA levels can affect the expression of gene products. There are seldom studies on the role of lncRNAs in inflammatory bowel disease (IBD). RESULTS: Quantitative RT-PCR showed that DQ786243 was significantly overexpressed in clinical active CD patients compared with clinical inactive CD patients (P = 0.0118) or healthy controls (P = 0.002). CREB was also more highly expressed in active CD than in inactive CD (P = 0.0034) or controls (P = 0.0241). Foxp3 was interestingly lower in inactive CD than in active CD (P = 0.0317) or controls (P = 0.0103), but there were no apparent differences between active CD and controls. CRP was well correlated with DQ786243 (r = 0.489, P = 0.034), CREB (r = 0.500, P = 0.029) and Foxp3 (r = 0.546, P = 0.016). At 48 hours after DQ786243 transfection, qRT-PCR showed both CREB (P = 0.017) and Foxp3 (P = 0.046) had an increased mRNA expression in Jurkat cells. Western blot showed the same pattern. After DQ786243 transfection, CREB phosphorylation ratio (p-CREB/t-CREB) was increased (P = 0.0043). CONCLUSION: DQ786243 can be related with severity of CD. It can affect the expression of CREB and Foxp3 through which regulates the function of Treg. CREB itself seems not the mediator of DQ786243 to up-regulate Foxp3. The phosphorylation of CREB might play a more important role in the process.

Transcribed ultraconserved region in human cancers.

Long non-coding RNAs (lncRNAs) are transcripts longer than ~200 nucleotides with little or no protein-coding capacity. Growing evidence shows that lncRNAs present important function in development and are associated with many human diseases such as cancers, Alzheimer disease, and heart diseases. Transcribed ultraconserved region (T-UCR) transcripts are a novel class of lncRNAs transcribed from ultraconserved regions (UCRs). UCRs are absolutely conserved (100%) between the orthologous regions of the human, rat, and mouse genomes. The UCRs are frequently located at fragile sites and at genomic regions involved in cancers. Recent data suggest that T-UCRs are altered at the transcriptional level in human tumorigenesis and the aberrant T-UCRs expression profiles can be used to differentiate human cancer types. The profound understanding of T-UCRs can throw new light on the pathogenesis of human cancers.

Computed tomography enterography versus balloon-assisted enteroscopy for evaluation of small bowel lesions in Crohn's disease.

BACKGROUND AND AIM: We aimed to assess the correlation between computed tomography enterography (CTE) and balloon-assisted enteroscopy on severity of small bowel lesions, and evaluated the accuracy of CTE parameters in assessing small intestine lesions in patients with Crohn's disease (CD). METHODS: We performed an observational study of a single-center cohort. Data were retrieved from our inpatient databases starting from October 2007. Correlations between computed tomography parameters (bowel wall thickness, mural enhancement, comb sign, extramural findings, and stricture), endoscopic and histological severity scores, CD Activity Index [CDAI], and C-reactive protein were assessed using Spearman's rank correlation. RESULTS: Seventy patients were included in this study. One hundred fifty-seven segments were examined. Bowel wall thickness (r = 0.6334, P < 0.0001), mural enhancement (r = 0.5477, P < 0.0001), comb sign (r = 0.5898, P < 0.0001), and extramural findings (r = 0.4754, P < 0.0001) were moderately correlated with the segmental Capsule Endoscopy CDAI. The segmental CTE score also moderately correlated with the segmental Capsule Endoscopy CDAI (r = 0.6714, P < 0.0001), while the total CTE score strongly correlated with the total Capsule Endoscopy CDAI (r = 0.7252, P < 0.0001). Both total CTE score (r = 0.5937, P < 0.0001) and total Capsule Endoscopy CDAI (r = 0.6364, P < 0.0001) correlated significantly with the Harvey-Bradshaw Index. Of five computed tomography parameters, bowel wall thickness have the best accuracy to detect small intestine lesions with an area under the receiver operating characteristic curve of 0.811 (P < 0.0001), with a sensitivity and specificity of 81.82% and 74.14%, respectively. CONCLUSION: CTE is a reliable technique for detecting small intestine lesions in patients with CD, also provides accurate information on small bowel CD severity and activity, with close agreement to inflammatory markers, CDAI, and histopathology.

Up-regulation and pre-activation of TRAF3 and TRAF5 in inflammatory bowel disease.

OBJECTIVE: TRAF3 and TRAF5 share a common ancestral gene, and interact as essential components of signaling pathways in immunity. TRAF3 and TRAF5 are overexpressed in the colon of rat/mouse models with colitis. However, the expressions of TRAF3 and TRAF5 in patients with inflammatory bowel disease have not been elucidated. The aim of the present study is to explore the potential roles of TRAF3 and TRAF5 in patients with inflammatory bowel disease. METHODS: Plasma levels of TRAF3 and TRAF5 proteins were detected by Enzyme-linked Immunosorbent Assay (ELISA). Colonic expression of TRAF3 and TRAF5 proteins was detected by western blot analysis. Quantitative Real-time PCR (qRT-PCR) was applied for gene expression. Inflamed intestinal mucosa and non-inflamed intestinal mucosa in patients with inflammatory bowel disease and normal mucosa was analyzed from healthy controls. RESULTS: The plasma levels of TRAF3 and TRAF5 were significantly higher both in patients with Crohn's disease and ulcerative colitis than in healthy controls. Only soluble TRAF5 showed a weak correlation with endoscopic disease activity index (Baron score) in patients with ulcerative colitis (spearman's r=0.358, P=0.022). Gene expressions of TRAF3 and TRAF5 in peripheral blood mononuclear cells were significantly higher both in patients with Crohn's disease and ulcerative colitis than in healthy controls (all P<0.0001). Gene and protein expressions of TRAF3 and TRAF5 were significantly higher in inflamed colonic mucosa of patients with Crohn's disease and ulcerative colitis than in non-inflamed colonic mucosa and normal mucosa of healthy controls (all P<0.0001). Furthermore, gene and protein expressions of TRAF3 and TRAF5 were also significantly higher in non-inflamed colonic mucosa of patients with Crohn's disease and ulcerative colitis than in normal mucosa of healthy controls. CONCLUSIONS: TRAF3 and TRAF5 are overexpressed in inflammatory bowel disease. Although the endoscopic appearance can be normal, TRAF3 and TRAF5 pre-activation can be detected in non-inflamed colonic segments.

Diagnosis of inflammatory bowel disease-Asian perspectives: the results of a multinational web-based survey in the 8th Asian Organization for Crohn's and Colitis meeting.

BACKGROUND/AIMS: Inflammatory bowel disease (IBD) is no longer a rare disease in Asia, thus it needs to prepare recommendations relevant to Asian patients. This study aimed to identify disparities in the process of the diagnosis of IBD in Asian countries/regions. METHODS: In line with the 2020 Asian Organization for Crohn's and Colitis annual meeting, a multinational web-based survey about Asian physicians' perspectives on IBD was conducted. RESULTS: A total of 384 Asian physicians (99 in China, 93 in Japan, 110 in Korea, and 82 in other Asian countries/regions) treating IBD patients from 24 countries/regions responded to the survey. Most respondents were gastroenterologists working in an academic teaching hospital. About half of them had more than 10 years of clinical experience in caring for patients with IBD. The European Crohn's Colitis Organisation guideline was used most commonly for the diagnosis of IBD except for Japanese physicians who preferred their own national guideline. The Mayo score and Crohn's Disease Activity Index were the most commonly used activity scoring systems for ulcerative colitis and Crohn's disease, respectively. Endoscopy, not surprisingly, was the main investigation in assessing the extent and activity of IBD. On the other hand, there were disparities across countries/regions with regard to the favored modalities of small bowel and perianal evaluation of Crohn's disease, as well as the use of serologic markers. CONCLUSIONS: Results of the present survey revealed practical behaviors of Asian physicians in the diagnosis of IBD. Investigating the reasons for different diagnostic approaches among countries/regions might help us develop Asian guidelines further.

The prevalence of Helicobacter pylori infection in inflammatory bowel disease in China: A case-control study.

BACKGROUND & AIMS: Helicobacter pylori (H. pylori) infection remains high in China though the incidence of inflammatory bowel disease (IBD) has increased. Our aim was to investigate the relationship between the prevalence of H. pylori and inflammatory bowel disease. METHODS: Hospitalized IBD patients including Crohn's disease (CD) and ulcerative colitis (UC) who had tested H. pylori antibody were enrolled. Controls were chose from age- and sex- matched healthy physical examination people who had H. pylori antibody test in a 1:2 fashion (IBD patients:controls). IBD medical history was recorded. All patients were typed by the Montreal classification. Mayo Clinic score and the Harvey-Bradshaw Severity Index were used to evaluate their disease activity. Patients and controls that had H. pylori eradication therapy before were excluded. RESULTS: Two hundred and sixty IBD patients including 213 CD patients and 47 UC patients, and 520 controls were involved in this study. The prevalence of H. pylori infection in IBD patients (9.6%, 25/260) and IBD newly diagnosed patients (12.1%, 8/66), as well as CD patients (8.9%, 19/213) including CD newly diagnosed patients (10.6%, 5/47) and UC patients (12.8%, 6/47) was significantly lower than controls (29.8%, 155/520) (p = 2.796*10-10, 0.007, 5.723*10-9, 0.016, 0.014), while there was no statistically difference between UC newly diagnosed patients and the controls, and IBD patients with different disease type, disease activity and treatment history. CONCLUSIONS: H. pylori infection had a negative association with IBD, especially CD.

Association of Serum Immunoglobulins Levels With Specific Disease Phenotypes of Crohn's Disease: A Multicenter Analysis in China.

Background and Aim: Serum immunoglobulins were reported to be associated with clinical characteristics of inflammatory bowel disease. However, whether a difference exists in the serum immunoglobulins levels in patients with Crohn's disease (CD) with different disease location and behavior phenotypes remains unclear. Therefore, this study aimed to explore the associations of serum immunoglobulins levels with specific CD phenotypes. Methods: Patients with CD having recorded serum immunoglobulins levels were recruited through multicenter collaborative efforts. The associations between serum immunoglobulins levels and distinct phenotypes of CD were evaluated using multiple logistic regression models. Results: A total of 608 patients with CD were included in the study. Elevated (above the upper limit of normal) serum immunoglobulin G (IgG), IgA, IgM, and IgG4 were identified in 24.5, 17.4, 2.1, and 8.2% of patients, respectively. Elevated serum IgG4 levels negatively correlated with complicated disease behavior [odds ratio (OR) 0.49, 95% confidence interval (CI) 0.26-0.92]. Elevated serum IgG was linked to isolated ileal disease with an OR of 0.37 (95% CI 0.23-0.61). The ORs of isolated ileal disease progressively reduced across increasing quartiles of IgG (P for trend < 0.001). The adjusted ORs of isolated ileal disease for increasing quartiles of IgM were 1.82 (1.07-3.1), 1.92 (1.14-3.24), 1.17 (0.69-1.98), and 1 (P for trend = 0.008). Besides, serum IgA and IgG levels significantly correlated with several disease activity indices. Conclusions: These results suggested that certain serum immunoglobulins were associated with specific disease phenotypes of CD. Further investigations to account for the associations are warranted.

Chromoendoscopy with targeted biopsies is superior to white-light endoscopy for the long-term follow-up detection of dysplasia in ulcerative colitis patients: a multicenter randomized-controlled trial.

BACKGROUND: Data from single-center experience or small sample-sized studies have shown that chromoendoscopy (CE) might be superior to white-light endoscopy (WLE) for dysplasia surveillance in ulcerative colitis (UC) patients. We performed a prospective randomized trial with a long-term follow-up to compare the detection rate of dysplasia among WLE with targeted biopsies (WLT), WLE with random biopsies (WLR), and dye-based CE with targeted biopsies (CET) in UC patients. METHODS: Patients with long-standing UC were enrolled from 11 medical centers from March 2012 to December 2013 and randomized into three arms (WLT, WLR, and CET). Only high-definition endoscopy was used in all three groups. The patients were followed up by annual endoscopy with biopsies through December 2017. RESULTS: With a median follow-up time of 55 months, a total of 122 patients with 447 colonoscopies were finally analysed in the per-protocol set: WLT (n = 43), WLR (n = 40), and CET (n = 39). A total of 34 dysplastic lesions were found in 29 colonoscopies of 21 patients. WLR and CET could identify more colonoscopies that diagnosed dysplasia than WLT (8.1% and 9.7% vs 1.9%; P = 0.014 and 0.004, respectively). WLR obtained more biopsied samples than WLT and CET (16.4 ± 5.1 vs 4.3 ± 1.4 and 4.3 ± 1.4; both P < 0.001). During the second half of the follow-up (37 - 69 months), CET could identify more colonoscopies that diagnosed dysplasia than WLT (13.3% vs 1.6%, P = 0.015) and showed a trend for increasing the detection rate compared with WLR (13.3% vs 4.9%, P = 0.107). CONCLUSIONS: For a better outcome of cancer/dysplasia surveillance in patients with long-standing UC, CET appeared to be more effective than WLT and less tedious than WLR. CET was found to be particularly useful when a long-term (>3 years) follow-up was conducted for dysplasia surveillance. The trial was registered on www.chictr.org.cn (ChiCTR1900023689).

NUDT15 genotyping during azathioprine treatment in patients with inflammatory bowel disease: implications for a dose-optimization strategy.

BACKGROUND: NUDT15 R139C is an Asian-prevalent genetic variant related to azathioprine (AZA) intolerance in patients with inflammatory bowel disease (IBD). However, it remains unclear how to utilize the genotyping results to improve the step-up dosing strategy with an already low starting dose in Asian practice. METHODS: Clinical data of eligible IBD patients who received AZA therapy and NUDT15 R139C testing were retrospectively collected. The relationship between NUDT15 genotype, AZA doses, and AZA-induced toxicity and efficacy were comprehensively analysed. RESULTS: A total of 159 patients were included for toxicity analysis. Compared with the wild genotype, patients heterozygous for R139C are more prone to developing myelotoxicity and alopecia (P = 0.007; P = 0.042). In particular, they had a 5.4-fold risk of developing myelotoxicity when AZA dosage was increased from 25 mg/d to 50 mg/d (P < 0.001). Regarding efficacy, 115 patients who had received AZA for >4 months and maintained clinical remission on AZA monotherapy were included for further analysis. R139C heterozygotes were finally titrated to a significantly lower dose than the wild genotype [median (interquartile range): 0.83 (0.75-0.96) vs 1.04 (0.89-1.33) mg/kg/d, P = 0.001], whereas the clinical remission rates did not differ between groups (P = 0.88). CONCLUSIONS: IBD patients with R139C heterozygote are highly susceptible to AZA-induced myelotoxicity at an escalated dose of 50 mg/d. Thus, they may require a smaller dose increase after a starting dose of 25 mg/d. The final target dose of these patients could be set lower than that of the wild genotypes without compromising efficacy.