Nomogram to predict primary non-response to infliximab in patients with Crohn's disease: a multicenter study.

BACKGROUND: Infliximab (IFX) is effective at inducing and maintaining clinical remission and mucosal healing in patients with Crohn's disease (CD); however, 9%-40% of patients do not respond to primary IFX treatment. This study aimed to construct and validate nomograms to predict IFX response in CD patients. METHODS: A total of 343 patients diagnosed with CD who had received IFX induction from four tertiary centers between September 2008 and September 2019 were enrolled in this study and randomly classified into a training cohort (n = 240) and a validation cohort (n = 103). The primary outcome was primary non-response (PNR) and the secondary outcome was mucosal healing (MH). Nomograms were constructed from the training cohort using multivariate logistic regression. Performance of nomograms was evaluated by area under the receiver-operating characteristic curve (AUC) and calibration curve. The clinical usefulness of nomograms was evaluated by decision-curve analysis. RESULTS: The nomogram for PNR was developed based on four independent predictors: age, C-reactive protein (CRP) at week 2, body mass index, and non-stricturing, non-penetrating behavior (B1). AUC was 0.77 in the training cohort and 0.76 in the validation cohort. The nomogram for MH included four independent factors: baseline Crohn's Disease Endoscopic Index of Severity, CRP at week 2, B1, and disease duration. AUC was 0.79 and 0.72 in the training and validation cohorts, respectively. The two nomograms showed good calibration in both cohorts and were superior to single factors and an existing matrix model. The decision curve indicated the clinical usefulness of the PNR nomogram. CONCLUSIONS: We established and validated nomograms for the prediction of PNR to IFX and MH in CD patients. This graphical tool is easy to use and will assist physicians in therapeutic decision-making.

Noncoding RNAs as Promising Diagnostic Biomarkers and Therapeutic Targets in Intestinal Fibrosis of Crohn's Disease: The Path From Bench to Bedside.

Fibrosis is a major pathway to organ injury and failure, accounting for more than one-third of deaths worldwide. Intestinal fibrosis causes irreversible and serious clinical complications, such as strictures and obstruction, secondary to a complex pathogenesis. Under the stimulation of profibrotic soluble factors, excessive activation of mesenchymal cells causes extracellular matrix deposition via canonical transforming growth factor-ß/Smads signaling or other pathways (eg, epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition) in intestinal fibrogenesis. In recent studies, the importance of noncoding RNAs (ncRNAs) stands out in fibrotic diseases in that ncRNAs exhibit a remarkable variety of biological functions in modulating the aforementioned fibrogenic responses. In this review, we summarize the role of ncRNAs, including the emerging long ncRNAs and circular RNAs, in intestinal fibrogenesis. Notably, the translational potential of ncRNAs as diagnostic biomarkers and therapeutic targets in the management of intestinal fibrosis is discussed based on clinical trials from fibrotic diseases in other organs. The main points of this review include the following: • Characteristics of ncRNAs and mechanisms of intestinal fibrogenesis • Wide participation of ncRNAs (especially the emerging long ncRNAs and circular RNAs) in intestinal fibrosis, including transforming growth factor-ß signaling, epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition, and extracellular matrix remodeling • Translational potential of ncRNAs in the diagnosis and treatment of intestinal fibrosis based on clinical trials from fibrotic diseases in other organs.

Classifying Crohn's disease into colon-involving versus non-colon-involving groups is a better predictor of clinical outcomes than the Montreal classification.

BACKGROUND: A suitable disease classification is essential for individualized therapy in patients with Crohn's disease (CD). Although a potential mechanistic classification of colon-involving and non-colon-involving disease was suggested by recent genetic and microbiota studies, the clinical implication has seldom been investigated. We aimed to explore the association of this colonic-based classification with clinical outcomes in patients with CD compared with the Montreal classification. METHODS: This was a retrospective study of CD patients from a tertiary referral center. Patients were categorized into colon-involving and non-colon-involving disease, and according to the Montreal classification. Clinico-demographic data, medications, and surgeries were compared between the two classifications. The primary outcome was the need for major abdominal surgery. RESULTS: Of 934 patients, those with colonic involvement had an earlier median (interquartile range) age of onset [23.0 (17.0-30.0) versus 26.0 (19.0-35.0) years, p = 0.001], higher frequency of perianal lesions (31.2% versus 14.5%, p < 0.001) and extraintestinal manifestations (21.8% versus 14.5%, p = 0.010), but lower frequency of stricture (B2) (16.3% versus 24.0%, p = 0.005), than those with non-colon-involving disease. Colon-involving disease was a protective factor against major abdominal surgery [hazard ratio, 0.689; 95% confidence interval (CI), 0.481-0.985; p = 0.041]. However, patients with colon-involving CD were more prone to steroids [odds ratio (OR), 1.793; 95% CI, 1.206-2.666; p = 0.004] and azathioprine/6-mercaptopurine (AZA/6-MP) treatment (OR, 1.732; 95% CI, 1.103-2.719; p = 0.017) than were patients with non-colon-involving disease. The Montreal classification was not predictive of surgery or steroids and AZA/6-MP treatment. CONCLUSION: This study supports the rationale for disease classification based on the involvement of colon. This new classification of CD is a better predictor of clinical outcomes than the Montreal classification.

Systematic review and meta-analysis: Association of a pre-illness Western dietary pattern with the risk of developing inflammatory bowel disease.

OBJECTIVE: Previous studies have presented conflicting results on Western diets and the risk of inflammatory bowel disease (IBD). This study aimed to evaluate the role of a pre-illness Western dietary pattern in the development of IBD. METHODS: The Western dietary pattern was defined as that met at least two of the following, either a high intake of refined grains, red and processed meat, animal protein, animal fats or high-fat dairy products, or with a low consumption of fruit and vegetables. Four medical databases (PubMed, EMBASE, the Cochrane Library and the China National Knowledge Infrastructure) were searched to identify all relevant references. Risk estimate and corresponding 95% confidence interval (CI) were pooled using a random-effects model. RESULTS: Nine studies (seven case-control studies and two prospective cohorts) were included, with a total of 1491 IBD cases and 53 089 controls. A Western dietary pattern was associated with a risk of all IBD (relative risk [RR] 1.92, 95% CI 1.37-2.68) and separately with Crohn's disease (CD) (RR 1.72, 95% CI 1.01-2.93) and ulcerative colitis (UC) (RR 2.15, 95% CI 1.38-3.34). Subgroup analysis by region showed that a Western dietary pattern was associated with the risk of CD and UC for studies performed in Europe (RR 2.25, 95% CI 1.44-3.50 for CD; RR 2.65, 95% CI 1.61-4.36 for UC). The pooled RR was 2.26 (95% CI 1.42-3.59) in the pediatric CD subgroup. CONCLUSION: This meta-analysis indicates that a pre-illness Western dietary pattern may increase the risk of developing CD and UC.

CYP2C19 polymorphism has no correlation with the efficacy and safety of thalidomide in the treatment of immune-related bowel disease.

OBJECTIVE: To explore the relationship between hepatic cytochrome P450 2C19 (CYP2C19) gene polymorphisms and the effectiveness and safety of thalidomide in the treatment of patients with immune-related bowel disease (IRBD). METHODS: CYP2C19 variants in 79 patients treated with thalidomide were analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The clinical response and adverse events of the thalidomide treatment were recorded. The potential influences of the CYP2C19 genotype polymorphisms on the clinical efficacy and adverse events of thalidomide were then investigated. RESULTS: Altogether 79 patients with IRBD (70 with Crohn's disease, three with ulcerative colitis and six with Behcet's disease) receiving thalidomide therapy were recruited from January 2013 to February 2015 in a tertiary IBD center in China. Overall, 21.5% (17/79) of these patients had CYP2C19 poor metabolizers genotype (PM). The overall response rate and the incidence of adverse events of CYP2C19 extensive metabolizers genotype were not significantly different from that of the PM when IRBD patients were treated with thalidomide (P = 0.517 and 0.816, respectively). CONCLUSION: CYP2C19 polymorphisms do not seem to be associated with efficacy of thalidomide and the incidence of adverse events in treating IRBD.

Low 6-thioguanine nucleotide level: Effective in maintaining remission in Chinese patients with Crohn's disease.

BACKGROUND AND AIM: Measuring 6-thioguanine nucleotide (6-TGN) level is useful in optimizing dose of azathioprine (AZA) and monitoring for toxicity. Lower dose of AZA was suggested for maintenance of clinical remission in Asian patients than Caucasian patients with Crohn's disease (CD). However, the optimal 6-TGN threshold required in Asian patients is undetermined. Therefore, the aim of the current study is to explore the optimal 6-TGN threshold required in Asian patients with CD for maintenance of clinical remission. METHODS: A retrospective cohort study in a tertiary referral center recruited 252 CD patients. The primary endpoint was disease relapse. The levels of 6-TGN and AZA dose were compared in remission group and relapse group. Remission rate was compared across the increased 6-TGN level and dose range. RESULTS: Patients with 6-TGN range of 0-180.94 pmol/8 × 108 red blood cells (RBC) had lower remission rate compared with those with 180.94-255.50 pmol/8 × 108 RBC (P = 0.020). Quartile analysis showed that increasing 6-TGN level beyond 180 pmol/8 × 108 RBC produced negligible gain in rate of remission. Frequency of adverse events significantly increased in patients with 6-TGN level > 355 pmol/8 × 108 RBC (8.0% with 6-TGN > 355 pmol/8 × 108 RBC vs 2.7% with 6-TGN < 355 pmol/8 × 108 RBC, P = 0.035). CONCLUSION: Our study suggested that optimal 6-TGN threshold required to maintain clinical remission in Chinese patients was 180-355 pmol/8 × 108 RBC.

Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?

BACKGROUND: The Montreal classification defines L4 Crohn's disease (CD) as any disease location proximal to the terminal ileum, which anatomically includes L4-esophagogastroduodenal (EGD), L4-jejunal, and L4-proximal ileal involvement. L4-jejunal disease was established to be associated with poor prognosis. However, the outcome of patients with L4-proximal ileal disease or L4-EGD remains to be clarified. Our study aimed to investigate whether the outcome differs among CD patients with L4-EGD, L4-jejunal, and L4-proximal ileal disease. METHODS: In our retrospective cohort study, 483 patients with confirmed CD were included. The primary outcome was intestinal surgery. Demographic features and outcomes were compared among L4-EGD, L4-jejunal, and L4-proximal ileal disease. RESULTS: Thirty-nine (8.1%) patients had isolated L4 disease, whereas 146 patients had L4 as well as concomitant L1, L2, or L3 disease. During a median follow up of 5.8 years, L4 patients were more likely to have intestinal surgeries compared to non-L4 patients (31% versus 16%, p < 0.001). The percentage of L4-jejunal patients who underwent surgery was higher than that of L4-proximal ileal (66% versus 28%, p < 0.001), and both of these subtypes of L4 were at higher risk for intestinal resection compared to L4-EGD patients (66% and 28% versus 9%, respectively, p < 0.001 and p < 0.05). On multi-variable analysis, L4-jejunal (HR 3.08; 95% CI 1.30-7.31) and L4-proximal ileal disease (HR 1.83; 95% CI 1.07-3.15) were independent predictors for intestinal resection. CONCLUSIONS: L4 disease had worse prognosis compared to non-L4 disease. Within L4 disease, phenotype of L4-jejunal and L4-proximal ileal disease indicated higher risk for intestinal surgery. It might be justified to further characterize the L4 phenotype of the Montreal classification into three specific subgroups including L4-EGD, L4-jejunal, and L4-proximal ileal disease, similar to the Paris classification of pediatric patients.

Heat shock protein family A member 6 combined with clinical characteristics for the differential diagnosis of intestinal Behçet's disease.

OBJECTIVE: To investigate the role of heat shock protein family A member 6 (HSPA6) expression alone and in combination with clinical characteristics in distinguishing intestinal Behçet's disease (BD) from Crohn's disease (CD) with ileocolonic involvement. METHODS: Patients diagnosed with either intestinal BD or CD were enrolled. Their clinical characteristics, disease activity, laboratory test results including hypersensitive C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR), endoscopic, pathological and radiological features were retrospectively analyzed. Enzyme-linked immunosorbent assay was applied to measure serum HSPA6 levels. RESULTS: Among intestinal BD patients, abdominal pain and diarrhea were the leading gastrointestinal symptoms. Submucosal lymphocyte infiltration was the most common pathological finding. Computed tomography enterography features involved number of segments of less than 4 and bowel wall thickening. Independent factors were round/ellipsoid intestinal ulcer (P < 0.001), number of ulcers ≤5 (P = 0.050), elevated ulcer margin (P = 0.019), absence of aphthous ulcer (P = 0.005), bowel wall thickening >13 mm (P < 0.001) and serum HSPA6 level >3.725 ng/mL (P = 0.008) for the differential diagnosis between intestinal BD and CD. Serum HSPA6 expression was significantly elevated in intestinal BD (0.72 ± 0.39 ng/mL) compared with CD (0.50 ± 0.24 ng/mL, P = 0.000) and healthy controls (0.38 ± 0.37 ng/mL, P = 0.000). CONCLUSION: HSPA6 in combination with clinical, radiological and pathological characteristics is useful in distinguishing intestinal BD from CD with ileocolonic involvement.

Prolonged azathioprine treatment reduces the need for surgery in early Crohn's disease.

BACKGROUND AND AIM: Whether an early use of azathioprine (AZA) can alter the natural history of Crohn's disease (CD) remains debated. The aim of this study is to evaluate the impact of AZA on disease progression in a cohort of patients with early CD. METHODS: This longitudinal cohort study examined patients with early CD defined as disease duration ≤ 18 months and no previous use of disease-modifying agents according to Paris definition. The primary outcome was the proportion of CD-related intestinal surgery. Cox regression analysis was performed to identify potential predictive factors of CD progression. RESULTS: One-hundred and ninety patients with early CD were enrolled in the study. After a median follow-up of 57 months (interquartile range, 31.3-76.2), 31 patients underwent abdominal surgeries, 48 patients were hospitalized, and 68 patients experienced clinical flares. The cumulative rate of remaining free of CD-related bowel surgery, hospitalization, and flare at 5 years on AZA treatment was 0.65, 0.59, and 0.39, respectively. Three independent predictors of CD-related operations were identified: prior bowel resection (hazard ratio [HR], 9.23; 95% confidence interval [CI] 3.67-23.23), smoker (HR, 4.0; 95% CI 1.38-11.65), and hemoglobin < 110 g/L at the time of initiation of AZA (HR, 4.36; 95% CI 1.80-10.58). Conversely, AZA treatment duration > 36 months (HR, 0.04; 95% CI 0.01-0.15) was associated with reduced CD-related operations. CONCLUSION: Prior bowel resection, smoking, and hemoglobin < 110 g/L at the time of initiation of AZA were risk factors associated with intestinal surgery in patients with early CD. However, prolonged use (≥ 36 months) of AZA was associated with a more favorable disease course of early CD.

Thiopurines prevented surgical recurrence in patients with Crohn's disease after intestinal resection: Strategy based on risk stratification.

BACKGROUND AND AIM: Thiopurines (TPs) are effective in reducing clinical and endoscopic recurrence in postoperative patients with Crohn's disease (CD). However, whether TPs could prevent surgical recurrence (SR) remains unknown. We aimed to explore whether TPs could prevent SR and identify risk factors associated with SR. METHODS: This was a retrospective cohort study of 246 postoperative patients with CD. Cox proportional hazard model was used to identify risk factors for SR. Patients were stratified according to the presence of risk factors. RESULTS: A total of 50 (20.3%) patients suffered SR after a mean follow up of 54.3±46.4 months. Multivariable analysis showed independent risk factors for SR were penetrating disease behavior (HR 8.628; 95% CI 1.573-47.341; P = 0.01), ileocolonic disease location (HR 2.597; 95% CI 1.047-6.445; P = 0.04) and isolated upper gastrointestinal disease (UGID) location (HR 5.082; 95% CI 1.496-17.267; P = 0.009). However, use of TPs after surgery significantly reduced the risk of SR (HR 0.120; 95% CI 0.063-0.231; P < 0.001). When stratifying patients according to risk factors, there was no statistical difference of SR between patients treated or not by TPs (P = 0.08) in low-risk group (n = 46). However, in high risk group (n = 200), patients with TPs use had a lower risk of SR than those without TPs (HR 0.093; 95% CI 0.048-0.178; P < 0.001). CONCLUSIONS: Penetrating disease behavior and ileocolonic/isolated (UGID) location were associated with SR in CD patients. TPs use was beneficial in decreasing risk for SR in CD patients at high risk.

Factors associated with the achievement of mucosal healing in Crohn's disease: the benefit of endoscopic monitoring in treating to target.

BACKGROUND: Mucosal healing (MH), the proposed treat to target in Crohn's disease (CD), is associated with improved disease outcomes. There are still scant data on factors associated with achieving MH in clinical practice. We evaluated the probability of achieving MH and identified factors predictive of subsequent MH in patients with CD. METHODS: This was a retrospective, observational cohort study. A total of 272 patients with CD with serial endoscopy assessment and subsequent therapeutic management were reviewed. The primary outcome was MH. The cumulative incidence of MH and endoscopic improvement was estimated using the Kaplan-Meier method. Factors independently associated with MH were identified using the Cox proportional hazards model. RESULTS: Of the 272 patients, 126 (46.32%) achieved MH after a median follow-up period of 33 months (interquartile range: 27-38 months). Factors independently associated with MH by multivariate analysis were time between endoscopic procedures within 26 weeks (hazard ratio [HR]: 1.56; 95% confidence interval [CI]: 1.05-3.39), adjustment of medical therapy when MH was not achieved (HR: 2.07; 95% CI: 1.26-2.33), prior enteric fistula (HR: 0.22; 95% CI: 0.06-0.91), perianal disease at CD diagnosis (HR: 0.58; 95% CI: 0.35-0.95), and C-reactive protein normalization within 12 weeks (HR: 3.23; 95% CI: 1.82-5.88). Similar factors have also been identified for endoscopic improvement. CONCLUSIONS: Performing serial endoscopic procedures at a 26-week interval and subsequent adjustment in medical treatment are helpful in achieving MH. Endoscopic monitoring plays an important role in the treating to target of CD.

Systematic review with meta-analysis: the efficacy and safety of stem cell therapy for Crohn's disease.

BACKGROUND AND AIMS: Stem cell therapy (SCT) for the treatment of Crohn's disease (CD) is still in its infancy, and whether SCT is associated with improved outcomes is unclear. We performed a meta-analysis to evaluate the efficacy and safety of patients receiving SCT. METHODS: Electronic databases were searched for studies that reported the use of stem cells for the treatment of patients with CD. Raw data from included studies were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes. RESULTS: We analyzed 21 studies comprising 514 patients with active CD. A random-effects meta-analysis of studies of SCT as systemic infusion showed 56% (95% confidence interval (CI) 33-76, n = 150) of patients achieved clinical response. Similarly, random-effects pooled rates of clinical or endoscopic remission were 46% (95% CI 25-69, n = 116) and 15% (95% CI 0-50, n = 48), respectively. A random-effects meta-analysis of all perianal CD studies showed that 57% (95% CI 44-69%, n = 251) of patients had healed fistula with SCT, with an odds ratio of 3.83 (95% CI 1.06-13.86, n = 121, P = 0.04) versus control. The pooled rate of clinical recurrence was high at 16% (95% CI 4-34, n = 101) with follow-up >12 months. The pooled rates of severe adverse events (SAEs) and SAEs related to SCT were 12% (95% CI 6-23, n = 378) and 8% (95% CI 3-18, n = 378), respectively. The Egger test suggests no publication bias existed for fistula healing (P = 0.36), but did for clinical response (P = 0.003). CONCLUSIONS: SCT seems potentially effective and may serve as an alternative treatment for refractory active CD. Toxicity will remain the most significant barrier to systemic SCT in patients with CD.

Thalidomide induces clinical remission and mucosal healing in adults with active Crohn's disease: a prospective open-label study.

BACKGROUND: Thalidomide is effective in inducing and maintaining clinical remission in children and adolescents with refractory Crohn's disease (CD). However, little is known about the efficacy and safety of thalidomide for adult patients with CD. METHODS: We conducted a prospective open-label cohort study between January 2013 and April 2015. A total of 47 adult patients with active CD who were dependent/resistant or intolerant to corticosteroids and/or immunomodulators or biologics received 50-100 mg of thalidomide daily. Primary outcome was clinical remission evaluated at week 8. Endoscopic assessment was performed at week 24 and defined as endoscopic response (decrease in Crohn's Disease Endoscopic Index of Severity [CDEIS] score > 5 points from baseline CDEIS of 6 or more), complete endoscopic remission (CDEIS score < 3), and mucosal healing (MH) (no ulceration). RESULTS: A total of 47 adults with active CD were enrolled. The clinical remission rate was 14.9% and 23.4% at week 4 and week 8, but increased to 46.8% at week 12 and 53.2% at week 24 out of all the 47 patients included (intention-to-treat analysis). Altogether 32 patients consented and underwent ileocolonoscopy at week 24. The rate of endoscopic response and complete endoscopic remission were 68.4% and 43.8%. MH (no ulceration) was achieved in 28.1% of patients. Adverse events occurred in 27/47 (57.4%) patients but necessitated therapy discontinuation in only 5/47 (10.6%) of patients. CONCLUSIONS: Low-dose thalidomide was effective and tolerated for inducing and maintaining clinical remission in adult patients with active CD, but the optimal time frame for thalidomide to induce clinical remission may be longer than previously appreciated and is probably optimal at 12 weeks. MH could reasonably be achievable with thalidomide.

Systematic review with meta-analysis: loss of response and requirement of anti-TNFα dose intensification in Crohn's disease.

BACKGROUND: To review the frequency with which anti-TNF-α loses its effect and dose "intensification" is required for Crohn's disease (CD) treatment. METHODS: Electronic databases were searched for eligible studies. Raw data from studies meeting inclusion criteria were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes. RESULTS: Eighty-six eligible studies were included. Estimates of loss of response (LOR) incidence ranged from 8 to 71%. The random effects pooled incidence of LOR with a median follow-up of 1-year was 33% (95% CI 29-38, 55 studies, n = 6135). The effect estimate based on data from patients with infliximab was 33% (95% CI 27-40), 30% (95% CI 22-39) for adalimumab, and 41% (95% CI 30-53) for certolizumabpegol. Overall, the mean percentage of patients' LOR to anti-TNFs was 38.5%. The annual risk for LOR was 20.9% per patient-year. The random-effects pooled rate of need for dose intensification with a median follow-up of 1 year was 34% (95% CI 28-41, 38 studies, n = 10,690). The effect estimate for infliximab was 38% (95% CI 28-50), 36% (95% CI 30-43) for adalimumab, and 2% (95% CI 2-3) for certolizumab-pegol. The mean percentage of patients who needed an anti-TNF dose escalation was 23% with an annual risk of 18.5% per patient-year. There was no evidence of publication bias for incidence of LOR but not for the dose intensification (p = 0.001). CONCLUSIONS: Overall, around one-third of CD patients experience a LOR and required dose intensification in primary anti-TNF-α responders.

Effects of Combination Therapy With Immunomodulators on Trough Levels and Antibodies Against Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Disease: A Meta-analysis.

BACKGROUND & AIMS: It is not clear whether combination therapy with immunomodulators affects the immunogenicity of tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel disease. We performed a meta-analysis to quantify the effects of combined immunomodulator therapy on the presence of antibodies against TNF antagonists (antidrug antibodies [ADAs]) and trough levels of anti-TNF agents. METHODS: We systematically searched publication databases for studies that reported prevalence of ADAs in patients who received anti-TNF agents. Raw data from studies that met the inclusion criteria were pooled to determine effect estimates. We performed subgroup and metaregression analyses to determine the level of heterogeneity among study outcomes. RESULTS: We analyzed findings from 35 studies that met inclusion criteria (results reported from 6790 patients with inflammatory bowel disease). The pooled risk ratio for formation of ADAs in patients receiving combined therapy with immunomodulators, versus that of patients receiving anti-TNF monotherapy, was 0.49 (95% confidence interval, 0.41-0.59; P < .001). However, the pooled analysis did not demonstrate a significant difference in trough levels of anti-TNF agents between patients with versus without concurrent use of immunomodulators (standardized mean difference, 0.11; 95% confidence interval, 0.19-0.41; P = .47). Subgroup analyses of patients treated with different TNF antagonists revealed no difference in the formation of ADAs (P = .50 for interaction); the protective effect of immunomodulators did not differ with type of drug patients were given (methotrexate vs thiopurines), or assay for ADA. We observed heterogeneity only among studies of patients with ulcerative colitis (I2 = 76%). Funnel plot and Egger test analyses indicated publication bias in the studies (P = .001). CONCLUSIONS: In a meta-analysis of published studies, we associated combined treatment with immunomodulators with reduced risk of formation of antibodies against TNF antagonists in patients with inflammatory bowel disease.

Over-reaching beyond disease activity: the influence of anxiety and medical economic burden on health-related quality of life in patients with inflammatory bowel disease.

PURPOSE: Many patients with inflammatory bowel disease (IBD) have impaired health-related quality of life (HRQOL). The influence of psychological and economic factors on HRQOL has not been fully elucidated in IBD. Therefore, we aimed to identify the predictors of HRQOL in an IBD cohort. PATIENTS AND METHODS: This was a cross-sectional cohort study of patients presenting to our tertiary IBD center. HRQOL was measured using the 36-item Short Form Health Survey (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ). Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). Perceived stress and perceived social support were also assessed by standardized scales. Demographic, socioeconomic and clinical data were obtained from a prespecified questionnaire and patients' medical records. Univariate analyses and multiple regression analysis were performed to identify predictors of HRQOL. RESULTS: A total of 242 IBD patients were recruited, and the questionnaire return rate was 90.5% (219/242). The prevalence rates of anxiety and depression were 24.7% and 17.4%, respectively. In all, 30.6% of the patients spent over half of their income to cover medical costs. Multivariate analysis revealed that anxiety symptoms (P<0.001), active disease (P<0.001) and higher medical expenditures (P=0.001) were strong and independent predictors of reduced HRQOL. CONCLUSION: Psychological factors and costs of medical care strongly impair HRQOL in IBD, independent of the disease activity. Psychological counseling and socioeconomic support programs should be considered for integration into the management of IBD patients.

Role of the microbiome in non-gastrointestinal cancers.

"The forgotten organ", the human microbiome, comprises a community of microorganisms that colonizes various sites of the human body. Through coevolution of bacteria, archaea and fungi with the human host over thousands of years, a complex host-microbiome relationship emerged in which many functions, including metabolism and immune responses, became codependent. This coupling becomes evident when disruption in the microbiome composition, termed dysbiosis, is mirrored by the development of pathologies in the host. Among the most serious consequences of dysbiosis, is the development of cancer. As many as 20% of total cancers worldwide are caused by a microbial agent. To date, a vast majority of microbiome-cancer studies focus solely on the microbiome of the large intestine and the development of gastrointestinal cancers. Here, we will review the available evidence implicating microbiome involvement in the development and progression of non-gastrointestinal cancers, while distinguishing between viral and bacterial drivers of cancer, as well as "local" and "systemic", "cancer-stimulating" and "cancer-suppressing" effects of the microbiome. Developing a system-wide approach to cancer-microbiome studies will be crucial in understanding how microbiome influences carcinogenesis, and may enable to employ microbiome-targeting approaches as part of cancer treatment.

Safety Profile of Thiopurines in Crohn Disease: Analysis of 893 Patient-Years Follow-Up in a Southern China Cohort.

Thiopurines have been associated with both clinical improvement and mucosal healing in treating Crohn disease (CD). Unfortunately, the high rate of adverse events (AEs) leading to drug withdrawal represents a major limitation in the use of these drugs.To evaluate the safety of thiopurines in patients with CD. To identify predictive factors associated with the development of thiopurine-induced AEs and withdrawal.This longitudinal cohort study examined patients from a university-based IBD referral center. Time-to-event analysis was performed with the Kaplan-Meier curve. Cox regression analysis was performed to identify potential predictive factors of AEs.Two hundred sixty-seven CD patients on thiopurines were included. A total of 143 AEs occurred at a median of 7.4 months (interquartile range, 3.7-15.3 months) after starting treatment. The cumulative incidence of AEs was 26%, with an annual risk of 4.3% per patient-year of treatment. The most frequent was leucopenia (41/267, 15.36%), followed by infections (29/267, 10.86%). Independent factors predictive of leucopenia were lower baseline hemoglobin (hazard ratio (HR), 0.34; 95% confidence interval (CI) 0.18-0.67) and the concomitant use of 5-aminosalicylic acid (HR, 3.05; 95% CI 1.44-8.76). Of the 28.44% (76/267) CD patients discontinued therapy, 14.61% due to AEs. A lower body mass index, the presence of extraintestinal manifestation, and the incidence of leucopenia independently predicted thiopurine withdrawal. In total, 37.5% of these patients restarted thiopurines and 52.3% of them had AEs again.About a quarter of patients on thiopurine therapy had AEs during follow-up and 1 of 7 patients had to discontinue thiopurines due to AEs.

Early Thiopurines Versus Conventional Step-Care Therapy for Modifying the Disease Course of Early Crohn's Disease: A Tertiary Referral Center Cohort Study.

The impact of thiopurines (TP) on the long-term outcome of early Crohn disease (CD) is still controversial. The present study designed as a comparison of conventional step-care to alternative treatment paradigms for disease progression.This longitudinal cohort study examined the established CD patients from a university-based inflammatory bowel disease referral center. Outcomes of mucosal healing (MH), CD-related surgery or hospitalization, and clinical remission were compared based on timing of initiation of TP therapy. The cumulative incidence of events was estimated by Kaplan-Meier method.One-hundred ninety patients with early CD were included. After a median follow-up of 57 months (interquartile range, 31.3-76.2), 29 patients undergone abdominal surgeries, 48 patients hospitalized, and 68 patients experienced clinical flares. A higher cumulative proportion of patients in the top-down (TD) group achieving MH than both the accelerated step-up (AC) group and conventional management (CM) group at month 36 (78.8% vs 39.9% and 42.2%, respectively; P = 0.001). There was a trend, albeit not significant, for an increased proportion of patients free of CD-related intestinal surgery in the TD group at month 60 (P = 0.16). However, among secondary outcomes, an early TP-based AC or TD strategy was not associated with improvement in clinical remission rates compared with a CM strategy at month 60 (P = 0.79). No significant difference was observed between early TP and CM for rates of MH, CD-related intestinal surgery or hospitalization, and clinical remission.Both AC and CM strategy were minimally effective for disease modification. TD strategy has the potential of achieving higher rates MH. Our results support the TD strategy in patients with early CD at risk for a disabling course.

Endoscopy Assessment at 1-Year Identifies Long-Term Responders to Thiopurines Maintenance Therapy in Patients With Crohn's Disease.

When treating Crohn disease (CD) with thiopurines, achievement of an objective response is essential. However, the minimal degree of mucosal improvement required to alter disease outcomes of CD is unknown.To determine the endoscopic responses of thiopurine monotherapy and to determine the minimal degree of mucosal improvement required to alter disease outcomes of CD.One hundred thirty CD patients who had evaluable ileocolonoscopy with evident of mucosal ulceration at baseline were included. The endpoints were endoscopic responses at the 2 follow-up endoscopies performed at 12 months (M12) and 36 month (M36) from the initiation of thiopurines.At M12, mucosal healing (MH) and a positive endoscopic response (PR) were documented in 38% and 46% of patients, respectively. At the second follow-up, merely a further 14% (13/93) of patients on monotherapy had a PR and a total of 46% (43/93) presented with MH. In a Cox regression model, both a PR (P < 0.02) and MH (P < 0.001) at M12 were associated with response at M36 in patients continuing thiopurine treatment. MH at M12 was associated with long-term disease outcomes of CD at M36, with an area under the Receiver Operator Characteristic curve of 0.54 for predicting clinical remission, 0.69 for hsCRP normalization, 0.69 for MH, and 0.74 for PR, respectively. A PR at M12, defined as a decrease in endoscopic activity score by ≥2 points from baseline, yielded similar results.Endoscopy at M12 can help to identify responders to thiopurine monotherapy in active CD. A PR could represent the minimal clinically important improvement in endoscopic disease activity.