Comparison and development of machine learning for thalidomide-induced peripheral neuropathy prediction of refractory Crohn's disease in Chinese population.

BACKGROUND: Thalidomide is an effective treatment for refractory Crohn's disease (CD). However, thalidomide-induced peripheral neuropathy (TiPN), which has a large individual variation, is a major cause of treatment failure. TiPN is rarely predictable and recognized, especially in CD. It is necessary to develop a risk model to predict TiPN occurrence. AIM: To develop and compare a predictive model of TiPN using machine learning based on comprehensive clinical and genetic variables. METHODS: A retrospective cohort of 164 CD patients from January 2016 to June 2022 was used to establish the model. The National Cancer Institute Common Toxicity Criteria Sensory Scale (version 4.0) was used to assess TiPN. With 18 clinical features and 150 genetic variables, five predictive models were established and evaluated by the confusion matrix receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), specificity, sensitivity (recall rate), precision, accuracy, and F1 score. RESULTS: The top-ranking five risk variables associated with TiPN were interleukin-12 rs1353248 [P = 0.0004, odds ratio (OR): 8.983, 95% confidence interval (CI): 2.497-30.90], dose (mg/d, P = 0.002), brain-derived neurotrophic factor (BDNF) rs2030324 (P = 0.001, OR: 3.164, 95%CI: 1.561-6.434), BDNF rs6265 (P = 0.001, OR: 3.150, 95%CI: 1.546-6.073) and BDNF rs11030104 (P = 0.001, OR: 3.091, 95%CI: 1.525-5.960). In the training set, gradient boosting decision tree (GBDT), extremely random trees (ET), random forest, logistic regression and extreme gradient boosting (XGBoost) obtained AUROC values > 0.90 and AUPRC > 0.87. Among these models, XGBoost and GBDT obtained the first two highest AUROC (0.90 and 1), AUPRC (0.98 and 1), accuracy (0.96 and 0.98), precision (0.90 and 0.95), F1 score (0.95 and 0.98), specificity (0.94 and 0.97), and sensitivity (1). In the validation set, XGBoost algorithm exhibited the best predictive performance with the highest specificity (0.857), accuracy (0.818), AUPRC (0.86) and AUROC (0.89). ET and GBDT obtained the highest sensitivity (1) and F1 score (0.8). Overall, compared with other state-of-the-art classifiers such as ET, GBDT and RF, XGBoost algorithm not only showed a more stable performance, but also yielded higher ROC-AUC and PRC-AUC scores, demonstrating its high accuracy in prediction of TiPN occurrence. CONCLUSION: The powerful XGBoost algorithm accurately predicts TiPN using 18 clinical features and 14 genetic variables. With the ability to identify high-risk patients using single nucleotide polymorphisms, it offers a feasible option for improving thalidomide efficacy in CD patients.

Clinical characteristics and risk factors of ovarian reserve decreases in women with Crohn's disease: a case-control study.

BACKGROUND: Crohn's disease (CD), often occurring in women of child-bearing age, can decline the fertility rate. However, whether it reduces ovarian reserve has been rarely reported. This study aimed to evaluate the ovarian reserve in women with CD from the perspective of anti-Müllerian hormone (AMH), and explore the factors that can decrease ovarian reserve. METHODS: A case-control retrospective study was designed. We analyzed the AMH levels in a total of 135 CD women and 878 healthy controls. Through propensity score matching, the subjects were assigned in a ratio of 1:3 to CD group (n = 121) and control group (n = 324). Both groups shared similar basic characteristics, like age, body mass index and smoking status. Serum AMH levels were measured by chemiluminescence. RESULTS: The AMH level in the CD group was significantly lower than that in the control group (2.17 ± 2.23 µg/L vs 3.95 ± 2.01 µg/L, 95%CI [1.34-2.21], P < 0.001). In both groups, the AMH levels decreased as age increased, but without between-group difference in the decreasing rate (P = 0.639). Multivariate analysis showed that age > 30 years (OR, 2.905; 95%CI [1.053-8.531], P = 0.017), disease activity (OR,4.314; 95%CI [1.561-12.910], P = 0.002) and thalidomide use (OR,12.628; 95%CI [4.351 -42.820], P < 0.001) were independent risk factors associated with decreased ovarian reserve (AMH<1.1µg/L). CONCLUSION: Ovarian reserve is lower in CD women than in healthy women. Age, CD activity and medication of thalidomide are risk factors that can aggravate the decline of ovarian reserve.

The efficacy and safety of thalidomide in the treatment of refractory Crohn's disease in adults: a double-center, double-blind, randomized-controlled trial.

Background: Thalidomide is applied in therapy for refractory Crohn's disease (CD) in adults, but systematic and rigorous clinical evidence is scant. The aim was to provide theoretical references for the efficacy of thalidomide in the therapy for refractory CD in adults. Methods: A double-center, double-blind, placebo-controlled, randomized clinical trial of refractory CD in adults in two inflammatory bowel disease centers in China. In the double-blind trial, patients were randomly assigned to 100 mg of thalidomide or placebo daily for 8 weeks. The primary outcome was considered as the clinical remission rate calculated based on the Crohn's disease activity index at the eighth week following thalidomide or placebo treatment. In open label, non-response to placebo was additionally treated with 8 weeks of thalidomide; all responders were continuously treated with thalidomide until the 48th week. Results: Twenty-five patients were randomly assigned to each group. At the eighth week, the clinical remission rate in the thalidomide group was significantly higher than that in the placebo group (68.0% [17/25] vs 16.0% [4/25]; relative risk, 4.2; 95% confidence interval, 1.8-10.9, P < 0.001). After a 48-week follow-up, the continuous treatment rate of thalidomide was 46.3% (19/41). Adverse events during the whole process were reported in 58.5% of patients, mainly involving drowsiness, rash, and peripheral neuropathy that were mild and tolerable. Conclusion: Thalidomide can be used in the induction and maintenance therapy of refractory CD in adults. And it could be one of the treatment options for refractory CD.

DNA-Thioguanine Nucleotides as a Marker for Thiopurine Induced Late Leukopenia after Dose Optimizing by NUDT15 C415T in Chinese Patients with IBD.

Thiopurine dose optimization by thiopurine-S-methyltransferase (TPMT) or nudix hydrolase-15 (NUDT15) significantly reduced early leucopenia in Asia. However, it fails to avoid the late incidence (> 2 months). Although laboratory monitoring of 6-thioguanine nucleotides (6TGN) to optimize thiopurine dose was suggested in White patients the exact association between leucopenia and 6TGN was controversial in Asian patients. In the present study, we aimed to explore whether DNA-thioguanine nucleotides (DNA-TGs) in leukocytes, compared with 6TGN in erythrocytes, can be a better biomarker for late leucopenia. This was a prospective, observational study. Patients with inflammatory bowel disease (IBD) prescribed thiopurine from February 2019 to December 2019 were recruited. Thiopurine dose was optimized by NUDT15 C415T (rs116855232). DNA-TG and 6TGN levels were determined at the time of late leucopenia or 2 months after the stable dose was obtained. A total of 308 patients were included. Thiopurine induced late leucopenia (white blood cells < 3.5 × 109 /L) were observed in 43 patients (14.0%), who had significantly higher DNA-TG concentration than those without leucopenia (P = 4.1 × 10-9 , 423.3 (~ 342.2 to 565.7) vs. 270.5 (~ 188.1 to 394.3) fmol/µg DNA). No difference in 6TGN concentrations between leucopenia and non-leucopenia was found. With a DNA-TG threshold of 340.1 fmol/µg DNA, 83.7% of leucopenia cases could be identified. Multivariate analysis showed that DNA-TG was an independent risk factor for late leucopenia. Quantification of DNA-TG, rather than 6TGN, can be applied to gauge thiopurine therapy after NUDT15 screening in Chinese patients with IBD.

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.

Xanthine oxidase activity in thiopurine curative Chinese inflammatory bowel disease patients.

Xanthine oxidase (XO) competes with thiopurine S-methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6-mercaptopurine (6-MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. We also evaluated whether a relationship between XO activity and incidence of thiopurine-induced adverse effects (AEs) existed. Clinical data and blood samples were collected from 140 IBD patients before receiving AZA/6-MP therapy, and the erythrocyte XO activity was measured. The XO activities of all patients were 20.29 ± 4.43 U/g Hb. No sex difference in XO activity was observed (p = .728), and the XO activity showed no difference between the UC and CD patients (p = .082). AEs were observed in 41 (29.3%) patients including leukopenia (26, 18.57%), gastrointestinal intolerance (11, 7.86%), flu-like symptom (5, 3.57%), alopecia (5, 3.57%), and hepatotoxicity (1, 0.71%). XO activity was significantly lower in the patients with AEs than in those without AEs (18.40 ± 3.73 vs. 21.07 ± 4.48 U/g Hb, p = .001), especially in the patients with leukopenia (18.29 ± 3.68 vs. 21.07 ± 4.48 U/g Hb, p = .004). However, no significant difference in XO activity was found between patients with and without other AEs. Decreased XO activity was observed in the patients who developed flu-like symptoms (17.58 ± 3.50 U/g Hb) and alopecia (18.67 ± 2.91 U/g Hb) compared to those who did not, although the differences did not reach statistical significance. These findings suggested that patients with low XO expression might have a high risk of thiopurine-induced toxicity.

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology practice recommendations for medical management and monitoring of inflammatory bowel disease in Asia.

Inflammatory bowel disease (IBD) has increased in incidence and prevalence in Asian countries since the end of the 20th century. Moreover, differences in the cause, phenotypes, and natural history of IBD between the East and West have been recognized. Therefore, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have established recommendations on medical management of IBD in Asia. Initially, the committee members drafted 40 recommendations, which were then assessed according to Grading of Recommendations Assessment, Development and Evaluation. Eight statements were rejected as this indicated that consensus had not been reached. The recommendations encompass pretreatment evaluation; medical management of active IBD; medical management of IBD in remission; management of IBD during the periconception period and pregnancy; surveillance strategies for colitis-associated cancer; monitoring side effects of thiopurines and methotrexate; and infections in IBD.

High-risk human papilloma virus infection and cervical neoplasm in female inflammatory bowel disease patients: a cross-sectional study.

BACKGROUND AND AIM: This cross-sectional study investigated the prevalence and risk factors of high-risk human papilloma virus (HPV) infection, especially types 16 and 18, and cervical neoplasia in female Inflammatory bowel disease (IBD) patients. METHODS: From July 2014 to January 2017, sexually active, female, Chinese IBD patients (21-60 years) and age-matched controls underwent cervical ThinPrep cytology testing (TCT) and high-risk HPV-DNA detection, and completed questionnaires about awareness of cervical cancer and HPV. Cervical dysplasia was categorized as cervical intraepithelial neoplasia (CIN) 1, 2 and 3. RESULTS: Of 124 IBD patients (30 ulcerative colitis and 94 Crohn's disease), 17 (13.7%) had high-risk HPV among whom 9 (7.3%) had HPV 16/18 infection and 4 (3.2%) had cervical CIN (3 CIN 3, 1 CIN 1) by pathology. Among 372 controls, 33 (8.9%) had high-risk HPV and only 1 (0.3%) had HPV 16 infection. Cervical TCT detected atypical squamous cells of unknown significance in one control; no control had CIN. The HPV 16/18 infection rate and CIN prevalence were significantly higher in IBD patients than controls (both P < 0.001). The HPV-infection rate was higher in patients administered methotrexate [P = 0.005, odds ratio (95% confidence interval) 4.76 (1.471-15.402)] or more than two immunosuppressants [P = 0.013, odds ratio (95% confidence interval) 3.64 (1.255-10.562)]. Thiopurine, steroid, infliximab and disease behavior/location were not associated with HPV infection. Only 29.3% of patients had undergone cervical-cancer screening. Awareness of HPV infection and HPV-related cervical cancer was poor (28.2%). CONCLUSIONS: Female IBD patients are at increased risk of high-risk HPV infection and cervical neoplasia, which may be associated with immunosuppressants. Education and routine follow-up with HPV-DNA testing and TCT are recommended, especially in female Chinese IBD patients.

Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn's disease patients.

BACKGROUND: Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes? AIM: To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes. METHODS: Patients' clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured. RESULTS: A total of 411 Crohn's disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively. CONCLUSION: The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.

Oral exclusive enteral nutrition induces mucosal and transmural healing in patients with Crohn's disease.

BACKGROUND AND AIMS: Mucosal healing is regarded as a clinical endpoint of Crohn's disease (CD), and transmural healing is correlated to the concept of deep remission. Current therapies to induce mucosal and transmural healing in CD are not satisfactory. Exclusive enteral nutrition (EEN) is underestimated therapy and its value has not been fully evaluated. Our aim was to investigate the efficacy of oral EEN for inducing mucosal and transmural healing in CD patients. METHODS: This was a prospective, single-center, open-label study including diagnosed CD children and adults conducted between January 2015 and December 2016 in the Sixth Affiliated Hospital of Sun Yat-sen University. All patients were treated with oral EEN and underwent paired assessment at baseline and completion using C-reaction protein, erythrocyte sedimentation rate, platelets, hemoglobin, body mass index, CD activity index, simple endoscopic score for CD and bowel sonography. Azathioprine was combined to prevent relapse. RESULTS: In this prospective observational study, 29 CD patients with an average age of 28.9 years were identified. After oral EEN treatment, 23 patients (79%) achieved complete mucosal healing, and the mean time to reach mucosal healing was 123 days (ranged from 50 to 212 days). Although only five patients (17%) achieved transmural healing, a significant reduction was observed in bowel-wall thickness (9.41 ± 3.06 vs 4.97 ± 1.76 mm, P < 0.001) and a significant improvement was observed in complications (including fistulas, abscess, ascites, stricture) assessed by bowel sonography (all P < 0.05). CONCLUSIONS: Oral EEN therapy is highly effective for inducing mucosal healing in CD patients. Both CD patients at active stage and those at clinical remission show excellent clinical response to oral EEN.

Risk factors for colorectal neoplasia in patients with underlying inflammatory bowel disease: a multicenter study.

BACKGROUND: This study sought to evaluate the risk factors for the development of colitis-associated neoplasia (CAN) in Chinese patients with inflammatory bowel disease (IBD). METHODS: IBD patients who developed CAN between 1999 and 2016 were identified from eight medical centers. In addition to initial pathology evaluation, a CAN diagnosis was confirmed by two expert pathologists. Patients with CAN (n = 29) were compared with non-CAN controls (n = 87). Matching was performed for gender and IBD type with a ratio of three controls to one subject. RESULTS: Of the 29 patients with CAN, 8 (27.6%) had colorectal cancer (CRC), 20 (69.0%) had a final diagnosis of low-grade dysplasia and 1 (3.4%) had high-grade dysplasia. Multivariate analysis revealed that an older age at the time of IBD diagnosis and a longer IBD duration were independent risk factors for the development of CAN, with odds ratios of 1.09 [95% confidence interval (CI): 1.04-1.14, P < 0.001] and 1.14 (95% CI: 1.03-1.27, P = 0.013), respectively. Comparison between IBD patients with CRC and those with dysplasia indicated that the former were older at the time of IBD diagnosis (P = 0.012) and had longer IBD durations (P = 0.019). CONCLUSIONS: Older age at the time of IBD diagnosis and longer IBD duration were found to be associated with the development of CAN in IBD patients.

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 1: risk assessment.

Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised 2 parts: risk of TB infection Recommendaduring anti-TNF therapy, and screening for TB infection prior to commencing anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 2: management.

Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised 3 parts: management of latent TB in preparation for anti-TNF therapy, monitoring during anti-TNF therapy, and management of an active TB infection after anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

Asian Organization for Crohn's and Colitis and Asian Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 1: Risk assessment.

Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asian Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection, and prevention of latent TB infection and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised two parts: (i) risk of TB infection during anti-TNF therapy and (ii) screening for TB infection prior to commencing anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 2: Management.

Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised three parts: (3) management of latent TB in preparation for anti-TNF therapy, (4) monitoring during anti-TNF therapy, and (5) management of an active TB infection after anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

Thalidomide results in diminished ovarian reserve in reproductive age female IBD patients.

The effectiveness of thalidomide in treating inflammatory bowel disease (IBD) has been widely recognized. Meanwhile, many serious adverse drug reactions have been observed, but no know reports on ovarian reserve function.Female patients, ranging in age between 18 and 40, were referred to our institution to undergo sex hormone detection and ultrasonic scanning for ovarian function assessment, between February 1, 2016 and September 31, 2016.Thirty-three patients treated with thalidomide (group A), 73 patients without thalidomide (group B), and 78 healthy women as control were studied. Menstrual disorder was higher in group A than group B (78.8% vs 57.2%, P < 0.05), and both groups were higher than control group 33.3%, P < 0.05. Anti-Mullerian hormone (AMH) levels and antral follicle count (AFC) in group A were lower than group B, P < 0.05, while estradiol (E2) and follicle-stimulating hormone (FSH) levels were no different between 2 groups. Crohn Disease Endoscopic Index of Severity (CDEIS) and thalidomide were the independent risk factors in diminished ovarian reserve (DOR), and when dose reached 75 mg/day, 5 g total, or when treatment time reached 10 months respectively. These influence may increasing (P < 0.05), but they may recover after stopping (P < 0.05).Thalidomide was an independent risk factor leading to DOR in female IBD patients, the influence may increasing when daily dose and accumulated dose reached 75 mg/day and 5 g total dose, but may be reversed by stopping.

Family history and disease outcomes in patients with Crohn's disease: A comparison between China and the United States.

AIM: To investigate the differences in family history of inflammatory bowel disease (IBD) and clinical outcomes among individuals with Crohn's disease (CD) residing in China and the United States. METHODS: We performed a survey-based cross-sectional study of participants with CD recruited from China and the United States. We compared the prevalence of IBD family history and history of ileal involvement, CD-related surgeries and IBD medications in China and the United States, adjusting for potential confounders. RESULTS: We recruited 49 participants from China and 145 from the United States. The prevalence of family history of IBD was significantly lower in China compared with the United States (China: 4.1%, United States: 39.3%). The three most commonly affected types of relatives were cousin, sibling, and parent in the United States compared with child and sibling in China. Ileal involvement (China: 63.3%, United States: 63.5%) and surgery for CD (China: 51.0%, United States: 49.7%) were nearly equivalent in the two countries. CONCLUSION: The lower prevalence of familial clustering of IBD in China may suggest that the etiology of CD is less attributed to genetic background or a family-shared environment compared with the United States. Despite the potential difference in etiology, surgery and ileal involvement were similar in the two countries. Examining the changes in family history during the continuing rise in IBD may provide further insight into the etiology of CD.

Standard-dose versus low-dose azathioprine in the treatment of Crohn's disease: A prospective randomized study.

OBJECTIVE: Azathioprine (AZA) is widely used to treat Crohn's disease (CD) with a recommended dose of 2-2.5 mg/kg per day for Westerners. Asian patients are suggested to take a lower dose. However, many clinicians reported poor efficacy with a reduced dose. This study aimed to explore a efficient and safe dose of AZA providing the best efficacy for Chinese CD patients. METHODS: Fifty patients with active CD were enrolled and randomized into two groups (n = 25 each). All other treatments were the same except that group A received 1 mg/kg per day and group B took 2 mg/kg per day of AZA. Complete remission (CR) rate and response rate at weeks 12, 24 and 48 were assessed by using intent-to-treat (ITT) and per-protocol (PP) analyses. Adverse events and recurrence rate were also evaluated. RESULTS: At week 48, CR rate and response rate in group B (ITT: 50.0% and 59.1%; PP: 57.9% and 68.4%) were significantly higher than those in group A (ITT: 13.0% and 17.4%; PP: 16.7% and 22.2%) (P < 0.05). Nine adverse events occurred, including pancreatitis (n = 1), arthritis (n = 2) and myelosuppression (n = 6). There was no significant difference in adverse events between the two groups. However, recurrence rate was significantly higher in group A than in group B (P = 0.042). CONCLUSION: AZA 2 mg/kg per day is more appropriate than 1 mg/kg per day for Chinese CD patients with a high efficacy, a low recurrence rate and not increased adverse events.

The Future of IBD Therapy: Where Are We and Where Should We Go Next?

BACKGROUND: The advent of biologic agents opens up a new era for the treatment of inflammatory bowel disease (IBD). In this era, the treatment goal has evolved from the traditional goal of clinical remission to a combination of clinical remission, laboratory normalization and mucosal healing, designated as 'complete deep remission'. Such complete deep remission comprises a more ambitious disease control strategy that is believed to probably modify the natural course of IBD. KEY MESSAGES: To achieve this goal, optimization of current strategy and introduction of novel therapies have gained significant interest. In this concise review, we aim to provide an overview of the current status and future direction of IBD treatment. Specifically, we will describe the application of personalized therapy, development of new biologics, intestinal microbiome manipulation and out-of-the-box agents for IBD. CONCLUSIONS: More evidence is still desirable to better optimize the current treatment and apply novel biologics. Personalized medicine has the potential to optimize efficacy, decrease the risk of adverse events and minimize costs and should be proposed as a standard of care for the management of IBD.

Macrophage migration inhibitory factor as a potential prognostic factor in gastric cancer.

AIM: To investigate macrophage migration inhibitory factor (MIF) expression and its clinical relevance in gastric cancer, and effects of MIF knockdown on proliferation of gastric cancer cells. METHODS: Tissue microarray containing 117 samples of gastric cancer and adjacent non-cancer normal tissues was studied for MIF expression by immunohistochemistry (IHC) semiquantitatively, and the association of MIF expression with clinical parameters was analyzed. MIF expression in gastric cancer cell lines was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Two pairs of siRNA targeting the MIF gene (MIF si-1 and MIF si-2) and one pair of scrambled siRNA as a negative control (NC) were designed and chemically synthesized. All siRNAs were transiently transfected in AGS cells with Oligofectamine(TM) to knock down the MIF expression, with the NC group and mock group (Oligofectamine(TM) alone) as controls. At 24, 48, and 72 h after transfection, MIF mRNA was analyzed by RT-PCR, and MIF and proliferating cell nuclear antigen (PCNA) proteins were detected by Western blot. The proliferative rate of AGS cells was assessed by methylthiazolyl tetrazolium (MTT) assay and colony forming assay. RESULTS: The tissue microarray was informative for IHC staining, in which the MIF expression in gastric cancer tissues was higher than that in adjacent non-cancer normal tissues (P < 0.001), and high level of MIF was related to poor tumor differentiation, advanced T stage, advanced tumor stage, lymph node metastasis, and poor patient survival (P < 0.05 for all). After siRNA transfection, MIF mRNA was measured by real-time PCR, and MIF protein and PCNA were assessed by Western blot analysis. We found that compared to the NC group and mock group, MIF expression was knocked down successfully in gastric cancer cells, and PCNA expression was downregulated with MIF knockdown as well. The cell counts and the doubling times were assayed by MTT 4 d after transfection, and colonies formed were assayed by colony forming assay 10 d after transfection; all these showed significant changes in gastric cancer cells transfected with specific siRNA compared with the control siRNA and mock groups (P < 0.001 for all). CONCLUSION: MIF could be of prognostic value in gastric cancer and might be a potential target for small-molecule therapy.