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    Development and Validation of a Test to Monitor Endoscopic Activity in Patients With Crohn's Disease Based on Serum Levels of Proteins. D'Haens Geert,Kelly Orlaith,Battat Robert,Silverberg Mark S,Laharie David,Louis Edouard,Savarino Edoardo,Bodini Giorgia,Yarur Andres,Boland Brigid S,Afif Waqqas,Li Xiao-Jun,Hale Michael,Ho Jessica,Kondragunta Venkateswarlu,Huang Benjamin,Kuy Crystal,Okada Lauren,Hester Kelly D,Bray Kurtis R,Mimms Larry,Jain Anjali,Singh Siddharth,Collins Angelina,Valasek Mark A,Sandborn William J,Vermeire Severine,Dulai Parambir S Gastroenterology BACKGROUND & AIMS:Noninvasive tests to measure endoscopic activity in patients with Crohn's disease (CD) have limitations. We aimed to develop a test to identify patients in remission, based on endoscopic analysis, and monitor CD activity based on serum levels of proteins. METHODS:We developed a test to measure 13 proteins in blood (ANG1, ANG2, CRP, SAA1, IL7, EMMPRIN, MMP1, MMP2, MMP3, MMP9, TGFA, CEACAM1, and VCAM1), called the endoscopic healing index [EHI], using samples from 278 patients with CD from a multinational training cohort. We validated the test using 2 independent cohorts of patients with CD: 116 biologic-naive patients with early-stage CD (validation cohort 1) and 195 biologic-exposed patients with chronic CD (validation cohort 2). The ability of the test to identify patients with active disease vs patients in remission (defined as a simple endoscopic score for CD of ≤2 and ≤1 in each segment, or a total CD endoscopic index of severity score <3) was assessed by using area under receiver operating characteristic curve (AUROC) analysis. The diagnostic accuracy of the test was compared with that of measurement of serum C-reactive protein (CRP) and fecal calprotectin. RESULTS:The EHI scores range from 0 to 100 units; higher scores indicate more severe CD activity, based on endoscopy findings. The EHI identified patients in remission with an AUROC of 0.962 in validation cohort 1 (95% confidence interval, 0.942-0.982) and an AUROC of 0.693 in validation cohort 2 (95% confidence interval, 0.619-0.767), regardless of CD location or phenotype. A cutoff value of 20 points identified patients in remission with the highest level of sensitivity (97.1% in validation cohort 1 and 83.2% in validation cohort 2), with specificity values of 69.0% and 36.6%, respectively. A cutoff value of 50 points identified patients in remission with the highest level of specificity (100% in validation cohort 1 and 87.8% in validation cohort 2), with sensitivity values of 37.3% and 30.0%, respectively. The EHI identified patients in remission with a significantly higher AUROC value than the test for CRP (0.876, P < .001 in validation cohort 1 and 0.624, P = .109 in validation cohort 2). In analysis of patients with available FC measurements, the AUROC value for the EHI did not differ significantly from that of measurement of FC (AUROC, 0.950 for EHI vs AUROC, 0.923 for FC; P = .147 in validation cohort 1 and AUROC, 0.803 for EHI vs AUROC, 0.854 for FC; P = .298 in validation cohort 2). CONCLUSIONS:We developed an index called the EHI to identify patients with CD in endoscopic remission based on blood levels of 13 proteins. The EHI identified patients with resolution of endoscopic disease activity, with good overall accuracy, although with variation between the 2 cohorts assessed. The EHI AUROC values were comparable to measurement of FC and higher than measurement of serum CRP. The test might be used in practice to assess endoscopic activity in patients with CD. 10.1053/j.gastro.2019.10.034
    Fecal calprotectin and S100A12 have low utility in prediction of small bowel Crohn's disease detected by wireless capsule endoscopy. Sipponen Taina,Haapamäki Johanna,Savilahti Erkki,Alfthan Henrik,Hämäläinen Esa,Rautiainen Henna,Koskenpato Jari,Nuutinen Hannu,Färkkilä Martti Scandinavian journal of gastroenterology OBJECTIVE:Data on fecal calprotectin and S100A12 in predicting wireless capsule endoscopy (WCE) findings in suspicion of Crohn's disease (CD) are scarce. Our aim was to study the role of calprotectin and S100A12 in predicting inflammatory lesions of small bowel in patients undergoing WCE. MATERIAL AND METHODS:84 patients undergoing WCE (77 for suspicion of CD and 7 CD patients for evaluation of disease extent) were prospectively recruited. WCE findings were scored. Patients provided a stool sample for measurements of biomarkers. Patients underwent an esophagogastroduodenoscopy and ileocolonoscopy before WCE. RESULTS:WCE was abnormal in 35 (42%) of 84 patients: 14 patients with CD, 8 with NSAID enteropathies, 8 with angioectasias, 4 with polyps or tumors, and 1 with ischemic stricture. Median calprotectin concentration in the study population was 22 μg/g (range 2-342) and S100A12 concentration 0.048 μg/g (range 0.003-1.215). Fecal calprotectin was significantly higher in CD patients (median 91, range 2-312) compared with those with normal WCE or other abnormalities (p = 0.008), whereas fecal S100A12 (0.087 μg/g, range 0.008-0.896) did not differ between the groups (p = 0.166). In detecting inflammatory small bowel lesions, sensitivity, specificity, positive predictive value, and negative predictive value for fecal calprotectin (cutoff 50 μg/g) were 59%, 71%, 42%, and 83%, and for S100A12 (cutoff 0.06 μg/g) these were 59%, 66%, 38%, and 82%. CONCLUSIONS:In predicting small bowel inflammatory changes, fecal biomarkers calprotectin and S100A12 have moderate specificity, but low sensitivity. Neither fecal calprotectin nor S100A12 can be used for screening or excluding small bowel CD. 10.3109/00365521.2012.677953
    Perianal Crohn disease: a new scoring system to evaluate and predict outcome of surgical intervention. Pikarsky Alon J,Gervaz Pascal,Wexner Steven D Archives of surgery (Chicago, Ill. : 1960) BACKGROUND:Conventional Crohn disease activity indices do not reflect perianal disease activity or allow prognostic implications from surgery. HYPOTHESIS:A new scoring system, based on the patient's disease history and physical examination findings, will allow more accurate use of surgical intervention for perianal Crohn disease. METHODS:A standardized scoring questionnaire was developed and applied to a consecutive group of patients before surgical treatment of perianal Crohn disease. The scoring system included abscess, fistula, ulcer and fissure, stenosis, incontinence, and concomitant disease. Weighted factors included acuity vs chronicity, de novo vs recurrent disease, and concomitant intestinal disease. The scoring system was validated against the surgical outcome, which was classified as poor, satisfactory, or good. RESULTS:Twenty-eight patients with Crohn disease who underwent 33 surgical procedures had a mean score of 16.5 (range, 3-37; possible range, 0-55). Using the Spearman nonparametric correlation test, the scoring system was accurate in predicting the outcome of surgical intervention (correlation coefficient, 0.78, 95% confidence interval, 0.57-0.89; P<.001) at mean follow-up of 20.8 months (range, 6-40 months). Correlation was further validated using a linear regression model (r = 0.75, slope best-fit value, 3.8; 95% confidence interval, 2.46-5.14; P<.001). All patients with a score of 10 or less had a good outcome, whereas all those with a score of 20 or greater had a poor outcome. CONCLUSIONS:The proposed scoring system correlated well with the short-term outcome of surgical intervention in patients with perianal Crohn disease and allowed prediction of surgical success. Ultimately, it may be possible to alter therapy based on preoperative prediction of the expected postoperative outcome. 10.1001/archsurg.137.7.774
    Evolutive pattern in Crohn's disease: a simplified index using clinical parameters predicts obstructive behaviour. Hinojosa J,Nos P,Ramírez J J,Hoyos M,Molés J R,Ponce J,Berenguer J European journal of gastroenterology & hepatology BACKGROUND:Two clearly differentiated evolutive patterns of Crohn's disease, obstructive and fistulizing, exist, but the early clinical parameters which can predict the evolution are unknown. AIM:To evaluate whether clinical variables, present at the time of diagnosis, may help in predicting a subsequent evolutive behaviour. PATIENTS AND METHODS:Ninety out of 140 evaluable patients were included. After a median of 50.2 months since diagnosis, 64 patients (71%) followed an obstructive pattern while 26 patients (28.9%) had a fistulizing form. Clinical variables were analysed as predictors of outcome. Logistic regression was carried out in order to obtain a mathematical model that would predict the evolution. The individual ability of the mathematical model to predict evolution was assessed using relative receiver operating characteristic (ROC) curves. RESULTS:The variables which were retained in the model were duration of disease before diagnosis (DD), onset of symptoms (OS), presence of anal disease (AD) and the presence of abdominal mass (AM). The equation z = -9.49 + 2.2643 (AD) - 0.0066 (DD) + 2.5282 (AM) + 1.3433 (OS) was obtained. The probability of evolution towards an obstructive form was P = 1/(1 + e(-Z)). This model can predict 96.88% of obstructive forms but only 53.85% of fistulizing forms. The mathematical point section (ROC curve) corresponds to a probability of 45.2%. Considering an obstructive pattern when the probabilities are above this point, the sensitivity is 98% and the specificity is 50%. CONCLUSIONS:The prediction of an obstructive pattern is feasible using simple clinical variables. The mathematical model obtained is useful for predicting this but not the fistulizing pattern.
    Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn's disease. Mazor Y,Almog R,Kopylov U,Ben Hur D,Blatt A,Dahan A,Waterman M,Ben-Horin S,Chowers Y Alimentary pharmacology & therapeutics BACKGROUND:Adalimumab is an effective treatment for Crohn's disease (CD). Anti-adalimumab antibodies (AAA) and low trough serum drug concentrations have been implicated as pre-disposing factors for treatment failure. AIMS:To assess adalimumab and AAA serum levels, and to examine their association and discriminatory ability with clinical response and serum C-reactive protein (CRP). METHODS:We performed a cross-sectional study using trough sera from adalimumab-treated CD patients. Demographical data, Montreal classification, treatment regimen and clinical status were recorded. Serum adalimumab, AAA and CRP were measured. Receiver operating characteristic analysis and a multivariate regression model were performed to find drug and antibody thresholds for predicting disease activity at time of serum sampling. RESULTS:One hundred and eighteen trough serum samples were included from 71 patients. High adalimumab trough serum concentration was associated with disease remission (Area Under Curve 0.748, P < 0.001). A cut-off drug level of 5.85 μg/mL yielded optimal sensitivity, specificity and positive likelihood ratio for remission prediction (68%, 70.6% and 2.3, respectively). AAA were inversely related with adalimumab drug levels (Spearman's r = -0.411, P < 0.001) and when subdivided into categorical values, positively related with disease activity (P < 0.001). High drug levels and stricturing vs. penetrating or inflammatory phenotype, but not AAA levels, independently predicted disease remission in a multivariate logistic regression model. CONCLUSIONS:Adalimumab drug levels were inversely related to disease activity. High levels of anti-adalimumab antibodies were positively associated with disease activity, but this association was mediated mostly by adalimumab drug levels. 10.1111/apt.12869
    Identifying Crohn's disease signal from variome analysis. Wang Yanran,Miller Maximilian,Astrakhan Yuri,Petersen Britt-Sabina,Schreiber Stefan,Franke Andre,Bromberg Yana Genome medicine BACKGROUND:After years of concentrated research efforts, the exact cause of Crohn's disease (CD) remains unknown. Its accurate diagnosis, however, helps in management and preventing the onset of disease. Genome-wide association studies have identified 241 CD loci, but these carry small log odds ratios and are thus diagnostically uninformative. METHODS:Here, we describe a machine learning method-AVA,Dx (Analysis of Variation for Association with Disease)-that uses exonic variants from whole exome or genome sequencing data to extract CD signal and predict CD status. Using the person-specific coding variation in genes from a panel of only 111 individuals, we built disease-prediction models informative of previously undiscovered disease genes. By additionally accounting for batch effects, we were able to accurately predict CD status for thousands of previously unseen individuals from other panels. RESULTS:AVA,Dx highlighted known CD genes including NOD2 and new potential CD genes. AVA,Dx identified 16% (at strict cutoff) of CD patients at 99% precision and 58% of the patients (at default cutoff) with 82% precision in over 3000 individuals from separately sequenced panels. CONCLUSIONS:Larger training panels and additional features, including other types of genetic variants and environmental factors, e.g., human-associated microbiota, may improve model performance. However, the results presented here already position AVA,Dx as both an effective method for revealing pathogenesis pathways and as a CD risk analysis tool, which can improve clinical diagnostic time and accuracy. Links to the AVA,Dx Docker image and the BitBucket source code are at https://bromberglab.org/project/avadx/ . 10.1186/s13073-019-0670-6
    A validated risk stratification tool for detecting high-risk small bowel Crohn's disease. Shen Eddie X,Lord Anton,Doecke James D,Hanigan Katherine,Irwin James,Cheng Richard K Y,Radford-Smith Graham Alimentary pharmacology & therapeutics BACKGROUND:Delays in Crohn's disease (CD) diagnosis are positively associated with ileal location and an increased risk of complications. AIM:To develop a simple risk assessment tool to enable primary care physicians to recognise potential ileal CD earlier, shortening the delay to specialist investigation METHODS: Three cohorts were acquired for this study. Cohort 1 included 61 patients retrospectively identified with ileal CD between 2000 and 2010 and 78 matched controls drawn from a cohort referred for investigation of abdominal symptoms. Cohort 2 included 42 individuals diagnosed with ileal CD and 57 controls identified prospectively. Cohort 3 included an additional 84 individuals with ileal CD and 495 without CD referred for colonoscopy. Clinical symptoms and serological biomarkers were acquired and used to develop a risk prediction algorithm. The algorithm was trained independently on each of the three cohorts and tested on the latter two cohorts. RESULTS:Altered bowel habit with abdominal pain combined with derangements in white cell count (WCC), albumin and platelet counts were important features in predicting ileal CD (AUC = 0.92, 95% CI = 0.89-0.92). This was validated in cohorts 2 (AUC = 0.96, 95% CI = 0.95-0.98) and 3 (AUC = 0.94, 95% CI = 0.92-0.96). C-reactive protein was independently associated with ileal CD but non-signficant in a multivariate model. CONCLUSION:A web-based risk stratification tool for ileal CD has been developed from objective and symptom-based criteria. This tool enables primary care physicians to more confidently request urgent specialist assessment for patients identified as at high risk for ileal CD. 10.1111/apt.15550
    Predicting the Individual Risk of Acute Severe Colitis at Diagnosis. Cesarini Monica,Collins Gary S,Rönnblom Anders,Santos Antonieta,Wang Lai Mun,Sjöberg Daniel,Parkes Miles,Keshav Satish,Travis Simon P L Journal of Crohn's & colitis Background and Aims :Acute severe colitis [ASC] is associated with major morbidity. We aimed to develop and externally validate an index that predicted ASC within 3 years of diagnosis. Methods:The development cohort included patients aged 16-89 years, diagnosed with ulcerative colitis [UC] in Oxford and followed for 3 years. Primary outcome was hospitalization for ASC, excluding patients admitted within 1 month of diagnosis. Multivariable logistic regression examined the adjusted association of seven risk factors with ASC. Backwards elimination produced a parsimonious model that was simplified to create an easy-to-use index. External validation occurred in separate cohorts from Cambridge, UK, and Uppsala, Sweden. Results:The development cohort [Oxford] included 34/111 patients who developed ASC within a median 14 months [range 1-29]. The final model applied the sum of 1 point each for extensive disease, C-reactive protein [CRP] > 10mg/l, or haemoglobin < 12g/dl F or < 14g/dl M at diagnosis, to give a score from 0/3 to 3/3. This predicted a 70% risk of developing ASC within 3 years [score 3/3]. Validation cohorts included different proportions with ASC [Cambridge = 25/96; Uppsala = 18/298]. Of those scoring 3/3 at diagnosis, 18/18 [Cambridge] and 12/13 [Uppsala] subsequently developed ASC. Discriminant ability [c-index, where 1.0 = perfect discrimination] was 0.81 [Oxford], 0.95 [Cambridge], 0.97 [Uppsala]. Internal validation using bootstrapping showed good calibration, with similar predicted risk across all cohorts. A nomogram predicted individual risk. Conclusions:An index applied at diagnosis reliably predicts the risk of ASC within 3 years in different populations. Patients with a score 3/3 at diagnosis may merit early immunomodulator therapy. 10.1093/ecco-jcc/jjw159
    Development and validation of predictive models for Crohn's disease patients with prothrombotic state: a 6-year clinical analysis. Pan Jianfeng,Lu Shuang,Li Yong,Li Zichun,Zhou Nan,Lian Guanghui,Liu Xiaowei Annals of palliative medicine BACKGROUND:Crohn's disease (CD) is a chronic idiopathic inflammatory disease. Studies show that multiple risk factors during disease progression can lead to a prothrombotic state (PTS), which predisposes the patient to thrombosis. Therefore, predicting PTS can help identify patients at risk of thrombosis. The aim of our study was to classify CD patients through D-dimer levels, and construct a prediction model for PTS. METHODS:The clinical and laboratory data parameters were extracted from a retrospective observational cohort. The factors significantly associated with PTS were determined by univariate analysis, and the importance rankings were calculated. Two multivariate models were then constructed using these factors to predict PTS in CD using logistic regression and random forest analysis. RESULTS:A total of 744 CD patients were included in the study, of which 116 were in PTS. The significant PTS-related factors were older patients, isolated colonic involvement, penetrating behavior, fever symptom, disease activity, abdominal surgery, lymphocyte counts, hematocrit levels, erythrocyte sedimentation rate, C-reactive protein, hematocrit, mean corpuscular volume levels and albumin. Multivariate logistic regression and random forest models predicted PTS with the accuracy of 89.73% and 90.63% respectively, and the corresponding AUC were 0.76 and 0.84. CONCLUSIONS:Two predictive models based on clinical and laboratory variables accurately identified CD patients with PTS with high precision. 10.21037/apm-20-875
    Predictive Factors for Differentiating Between Crohn's Disease and Intestinal Tuberculosis in Koreans. Jung Yunho,Hwangbo Young,Yoon Soon Man,Koo Hoon Sup,Shin Hyun Deok,Shin Jeong Eun,Moon Hee Seok,Kang Sang Bum,Lee Jeong Rok,Huh Kyu Chan The American journal of gastroenterology OBJECTIVES:A differential diagnosis between intestinal tuberculosis (ITB) and Crohn's disease (CD) is challenging. The aim of this study was to investigate the clinical, endoscopic, and histological features and to create a predictive score model for differentiating CD and ITB. METHODS:In total, 261 patients, 99 with ITB and 162 with CD, were recruited from seven tertiary centers from 2005 to 2013 and reviewed retrospectively. For the creation of a validated model, parameters were selected by univariate logistic regression and receiver operating characteristic curve analyses. Then, the prediction model was established on the basis of β-coefficients of the multivariate logistic regression. For the validation of the model, the same regression equation was tested on the other group. RESULTS:Age, diarrhea, ring-shaped ulcer, longitudinal ulcer, sigmoid involvement, suspicious radiological pulmonary tuberculosis, and gender were selected as the factors for a seven-marker model. In the seven-marker model of the validation data set, the sensitivity, specificity, positive predictive value, and negative predictive value with a cutoff level of 0.35 were 98.0, 92.4, 88.9, and 98.6, respectively. CONCLUSIONS:The seven-marker model seems to be highly reliable for differentiating between ITB and CD and could be conveniently used by clinicians to obtain results. 10.1038/ajg.2016.212
    Fecal calprotectin and lactoferrin as predictors of relapse in patients with quiescent ulcerative colitis during maintenance therapy. Yamamoto Takayuki,Shiraki Manabu,Bamba Takuya,Umegae Satoru,Matsumoto Koichi International journal of colorectal disease PURPOSE:This prospective study was to evaluate the significance of fecal calprotectin and lactoferrin for the prediction of ulcerative colitis (UC) relapse. METHODS:Eighty UC patients in remission for ≥3 months on mesalamine as maintenance therapy were included. At entry, stool samples were collected for the measurement of calprotectin and lactoferrin. All patients were followed up for the following 12 months. To identify predictive factors for relapse, time-dependent analyses using the Kaplan-Meier graphs and Cox's proportional hazard model were applied. RESULTS:During the 12 months, 21 patients relapsed. Mean calprotectin and lactoferrin levels were significantly higher in patients with relapse than those in remission (calprotectin-173.7 vs 135.5 μg/g, P = 0.02; lactoferrin-165.1 vs 130.7 μg/g, P = 0.03). A cutoff value of 170 μg/g for calprotectin had a sensitivity of 76 % and a specificity of 76 % to predict relapse, while a cutoff value of 140 μg/g for lactoferrin had a sensitivity of 67 % and a specificity of 68 %. In a multivariate analysis, calprotectin (≥170 μg/g) was a predictor of relapse (hazard ratio, 7.23; P = 0.002). None of the following parameters were significantly associated with relapse: age, gender, duration of UC, number of UC episode, severity of the previous episode, extent of UC, extraintestinal manifestation, and lactoferrin level. CONCLUSIONS:Fecal calprotectin showed a higher sensitivity and specificity than fecal lactoferrin for predicting UC relapse. Fecal calprotectin level appeared to be a significant predictor of relapse in patients with quiescent UC on mesalamine as maintenance therapy. 10.1007/s00384-013-1817-3
    Genetic risk profiling and prediction of disease course in Crohn's disease patients. Henckaerts Liesbet,Van Steen Kristel,Verstreken Isabel,Cleynen Isabelle,Franke Andre,Schreiber Stefan,Rutgeerts Paul,Vermeire Séverine Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:Clinical presentation at diagnosis and disease course of Crohn's disease (CD) are heterogeneous and variable over time. Early introduction of immunomodulators and/or biologicals might be justified in patients at risk for disease progression, so it is important to identify these patients as soon as possible. We examined the influence of recently discovered CD-associated susceptibility loci on changes in disease behavior and evaluated whether a genetic risk model for disease progression could be generated. METHODS:Complete medical data were available for 875 CD patients (median follow-up time, 14 years; interquartile range, 7-22). Fifty CD-associated polymorphisms were genotyped. Kaplan-Meier survival analyses, multiple logistic regression, and generalized multifactor dimensionality reduction analyses (GMDR) were performed, correcting for follow-up time. RESULTS:Homozygosity for the rs1363670 G-allele in a gene encoding a hypothetical protein near the IL12B gene was independently associated with stricturing disease behavior (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.60-18.83; P = .007) and with shorter time to strictures (P = .01), especially in patients with ileal involvement (P = .0002). Male patients carrying at least one rs12704036 T-allele in a gene desert had the shortest time to non-perianal fistula (P < .0001). The presence of a C-allele at the CDKAL1 single nucleotide polymorphism rs6908425 and the absence of NOD2 variants were independently associated with development of perianal fistula (OR, 8.86; 95% CI, 1.13-69.78; P = .04 and OR, 0.56; 95% CI, 0.38-0.83; P = .004, respectively), particularly when colonic involvement and active smoking were present. CONCLUSIONS:CD-associated polymorphisms play a role in disease progression and might be useful in identifying patients who could benefit from an early top-down treatment approach. 10.1016/j.cgh.2009.05.001
    Analysis of Phenotypic Variables and Differentiation Between Untypical Crohn's Disease and Untypical Intestinal Tuberculosis. Meng Yu,Li Ying,Hao Rong,Li Xiaojun,Lu Fanggen Digestive diseases and sciences BACKGROUND:The differentiation between untypical intestinal tuberculosis (UITB) and untypical Crohn's disease (UCD) is a challenge. AIMS:To analyze phenotypic variables and propose a novel prediction model for differential diagnosis of two conditions. METHODS:A total of 192 patients were prospectively enrolled. The clinical, laboratory, endoscopic, and radiological features were investigated and subjected to univariable and multivariable analyses. The final prediction model for differentiation between UCD and UITB was developed by logistic regression analysis and Fisher discriminant analysis on the training set. The same discriminant function was tested on the validation set. RESULTS:Twenty-five candidates were selected from 52 phenotypic variables of typical Crohn's disease (TCD), UCD, and UITB patients. UCD's variables overlapped with both TCD and UITB. The percentages of tuberculosis history, positive PPD, and positive T-SPOT result in UCD were all significantly higher than that in TCD (11.6% vs. 0.0%, 27.9% vs. 0.0%, 25.6% vs. 4.5%, respectively, P < 0.05). The regression equations and Fisher discriminant function for discrimination between UCD and UITB were developed. In the training data, the area under the receiver operating characteristic of equations was 0.834, 0.69, and 0.648 in the clinical-laboratory, endoscopic, and radiological model, respectively. The accuracy of Fisher discriminant function for discrimination was 86% in UCD and 73% in UITB in the validation data. CONCLUSIONS:Phenotypes of UCD patients in TB-endemic countries may be associated with TB infection history. Fisher discriminant analysis is a good choice to differentiate UCD from UITB, which is worthy of verification in clinical practice. 10.1007/s10620-019-05491-z
    Performance of a Deep Learning Model vs Human Reviewers in Grading Endoscopic Disease Severity of Patients With Ulcerative Colitis. Stidham Ryan W,Liu Wenshuo,Bishu Shrinivas,Rice Michael D,Higgins Peter D R,Zhu Ji,Nallamothu Brahmajee K,Waljee Akbar K JAMA network open Importance:Assessing endoscopic disease severity in ulcerative colitis (UC) is a key element in determining therapeutic response, but its use in clinical practice is limited by the requirement for experienced human reviewers. Objective:To determine whether deep learning models can grade the endoscopic severity of UC as well as experienced human reviewers. Design, Setting, and Participants:In this diagnostic study, retrospective grading of endoscopic images using the 4-level Mayo subscore was performed by 2 independent reviewers with score discrepancies adjudicated by a third reviewer. Using 16 514 images from 3082 patients with UC who underwent colonoscopy at a single tertiary care referral center in the United States between January 1, 2007, and December 31, 2017, a 159-layer convolutional neural network (CNN) was constructed as a deep learning model to train and categorize images into 2 clinically relevant groups: remission (Mayo subscore 0 or 1) and moderate to severe disease (Mayo subscore, 2 or 3). Ninety percent of the cohort was used to build the model and 10% was used to test it; the process was repeated 10 times. A set of 30 full-motion colonoscopy videos, unseen by the model, was then used for external validation to mimic real-world application. Main Outcomes and Measures:Model performance was assessed using area under the receiver operating curve (AUROC), sensitivity and specificity, positive predictive value (PPV), and negative predictive value (NPV). Kappa statistics (κ) were used to measure agreement of the CNN relative to adjudicated human reference cores. Results:The authors included 16 514 images from 3082 unique patients (median [IQR] age, 41.3 [26.1-61.8] years, 1678 [54.4%] female), with 3980 images (24.1%) classified as moderate-to-severe disease by the adjudicated reference score. The CNN was excellent for distinguishing endoscopic remission from moderate-to-severe disease with an AUROC of 0.966 (95% CI, 0.967-0.972); a PPV of 0.87 (95% CI, 0.85-0.88) with a sensitivity of 83.0% (95% CI, 80.8%-85.4%) and specificty of 96.0% (95% CI, 95.1%-97.1%); and NPV of 0.94 (95% CI, 0.93-0.95). Weighted κ agreement between the CNN and the adjudicated reference score was also good for identifying exact Mayo subscores (κ = 0.84; 95% CI, 0.83-0.86) and was similar to the agreement between experienced reviewers (κ = 0.86; 95% CI, 0.85-0.87). Applying the CNN to entire colonoscopy videos had similar accuracy for identifying moderate to severe disease (AUROC, 0.97; 95% CI, 0.963-0.969). Conclusions and Relevance:This study found that deep learning model performance was similar to experienced human reviewers in grading endoscopic severity of UC. Given its scalability, this approach could improve the use of colonoscopy for UC in both research and routine practice. 10.1001/jamanetworkopen.2019.3963
    Prediction of disease complication occurrence in Crohn's disease using phenotype and genotype parameters at diagnosis. Mazor Yoav,Maza Itay,Kaufman Eduard,Ben-Horin Shomron,Karban Amir,Chowers Yehuda,Eliakim Rami Journal of Crohn's & colitis BACKGROUND AND AIMS:Complications associated with Crohn's disease (CD) are common and influence treatment decisions and outcomes. Appropriate early treatment may offer a therapeutic advantage to patients. The aim of our study was to indentify predictive factors for occurrence of complications at the time of CD diagnosis. METHODS:The study population consisted of 269 CD patients treated during a ten year period. Risk factors compared between complicated and non-complicated disease included phenotypical characteristics, disease classification and the presence of NOD2/CARD15 mutations and single nucleotide polymorphisms in selected autophagy and phagosome genes. RESULTS:Complete data was obtained for 146 patients with an average follow up of 12years. Sixty five patients (44%) developed a complication during follow up. The only independent risk factors associated with developing a complication were smoking and male gender. There was no association between developing complications and the presence of selected SNPs (P=0.07 for Tyrosine residue on both alleles in NCF4 SNP rs4821544 and P=0.06 for a Guanine residue on both alleles in ATG16L SNP rs2241880). Multivariate analysis using a backwards logistic regression model left only male gender as an independent statistically significant association with complicated disease (OR 2.6017, 95% CI: 1.17 to 5.75). The median time to developing a complication was 4years, and the most common complication was the need for surgical intervention (54%). CONCLUSIONS:In the present study, a risk factor for developing CD complication was male gender. Further studies are warranted to assess additional risk factors and how such findings should affect therapy. 10.1016/j.crohns.2011.06.002
    Antinuclear antibodies: a marker associated with steroid dependence in patients with ulcerative colitis. Barahona-Garrido J,Camacho-Escobedo J,García-Martínez C I,Tocay H,Cabiedes J,Yamamoto-Furusho J K Inflammatory bowel diseases BACKGROUND:The autoimmune phenomena and the autoantibody profile have acquired great importance in ulcerative colitis (UC). Few studies have explored antinuclear antibodies (ANAs) prevalence, but not its association with steroid dependence. We hypothesized that ANAs could be a factor associated to steroid dependence. METHODS:Ninety-seven consecutive patients with UC were included. ANA titers and staining patterns were determined by indirect immunofluorescence. Gender, age, follow-up time, C-reactive protein (CRP), disease extent, Mayo Score Activity Index, extraintestinal manifestations, and steroid dependence were analyzed in univariate and multivariate models. RESULTS:Ninety-seven patients were included and 49 (50.5%) were females; mean age was 41.7 +/- 22.2 years. Positivity for ANAs was encountered in 52 (53.5%) patients, and none for anti-dsDNA. The prevalence of ANAs was higher in steroid-dependent than in nonsteroid-dependent patients (77.8% versus 48.1%, P = 0.020; odds ratio [OR] = 3.8, 95% confidence interval [CI] 1.1-12.5), and in those with uveitis (100% versus 51.1%; P = 0.040) or pyoderma gangrenosum (100% versus 51.6%; P = 0.078). No association was observed with gender, age, CRP, disease extent, and Mayo Score Activity Index. The multiple regression analysis model showed an association between steroid dependence and ANAs (P = 0.033, OR = 3.9, 95% CI 1.4-14.9). CONCLUSIONS:ANAs are associated with steroid dependence in UC patients. Further studies are required to determine the role of ANAs as serological markers for prediction of steroid dependence in order to perform early therapeutic interventions with biological agents. 10.1002/ibd.20852
    A New Model Based on 25-Hydroxyvitamin D3 for Predicting Active Crohn's Disease in Chinese Patients. Lin Sinan,Wang Ying,Li Li,Chen Peng,Mao Ren,Feng Rui,Qiu Yun,He Yao,Chen Baili,Zeng Zhirong,Chen Minhu,Zhang Shenghong Mediators of inflammation Background:The association between vitamin D3 and activity of Crohn's disease (CD) is unclear in Chinese patients. In this study, we aimed to evaluate the correlations between serum levels of 25-hydroxyvitamin D3 (25(OH)D3) and disease activity and predict active disease based on vitamin D status. Methods:Between January 2014 and December 2017, 346 CD patients from the First Affiliated Hospital of Sun Yat-sen University were recruited and categorized into a group with 25(OH)D3 ≤ 20 ng/ml and a group with 25(OH)D3 > 20 ng/ml. The clinical characteristics, medication, and health-care needs were compared between the groups. The correlations among 25(OH)D3 and routine serum biomarkers and disease activity were examined. The predictive efficiency of 25(OH)D3 and other biomarkers for active diseases was also explored using receiver-operating characteristic (ROC) curve analysis. A new predictive model, -(525(OH)D3 + 2Hb) + ESR, and a nomogram were established using Logistic Regression. Results:Patients with 25(OH)D3 ≤ 20 ng/ml had higher serum levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and platelets (PLT) and lower levels of hemoglobin (Hb) and albumin (ALB). Serum levels of 25(OH)D3 were inversely correlated with the score of Crohn's Disease Activity Index (CDAI) ( = -0.608). ROC analysis showed a better predictive value of -25(OH)D3 and the new model with areas under curve (AUC) of 0.804 and 0.879, respectively, than those of CRP (0.693) and ESR (0.713) in disease activity. A nomogram for prediction was established with a c-index of 0.882. Conclusions:Serum levels of 25(OH)D3 negatively correlated with CD activity in Chinese patients. The new model and a nomogram based on 25(OH)D3 showed a better efficiency in predicting disease activity in CD patients but warrants further study. 10.1155/2018/3275025
    Predictive parameters for the clinical course of Crohn's disease: development of a simple and reliable risk model. Stallmach Andreas,Bokemeyer Bernd,Helwig Ulf,Lügering Andreas,Teich Niels,Fischer Imma,Rath Stefan,Lang Dorothee,Schmidt Carsten, International journal of colorectal disease PURPOSE:The aim of our study was to identify clinical parameters in recently diagnosed Crohn's disease (CD) patients for prediction of their disease course. METHODS:EPIC (Early Predictive parameters of Immunosuppressive therapy in Crohn's disease) is a prospective, observational study in 341 patients with a recent CD diagnosis (≤ 6 months), and naïve to immunosuppressants (IS) and anti-tumor necrosis factor α (TNF) agents. Patient characteristics were documented up to 2 years. In line with national and international guidelines, a complicated disease course was defined as need for immunosuppressants and/or anti-TNF agents, and CD-related hospitalization with or without immunosuppressants and/or anti-TNF agents. RESULTS:A total of 212 CD patients were analyzed of whom 57 (27%) had an uncomplicated disease within 24 months, while 155 (73%) had a complicated disease course: need for IS and/or anti-TNF agents (N = 115), CD-related hospitalization with or without IS/anti-TNF agents (N = 40). Identified risk predictors for a complicated disease were as follows: age at onset < 40 years (OR 2.3; 95% CI 1.2-4.5), anemia (OR 2.1; 95% CI 1.1-4.2), and treatment with systemic corticosteroids at first flare (OR 2.2; 95% CI 1.1-4.7). These three parameters were used to develop a risk model allowing prediction of the future disease course. CONCLUSION:Our three-parameter model enables an assessment of each CD patient's risk to develop a complicated disease course. Due to the easy accessibility of these parameters, this model can be utilized in daily clinical care to assist selecting the initial treatment for each individual patient. 10.1007/s00384-019-03369-0
    Early histological findings quantified by histomorphometry allow prediction of clinical phenotypes in Crohn's colitis patients. Klein Amir,Eliakim Rami,Karban Amir,Mazor Yoav,Ben-Izhak Ofer,Chowers Yehuda,Sabo Edmond Analytical and quantitative cytopathology and histopathology OBJECTIVE:To evaluate the histomorphometric features of early colonic biopsies from patients with Crohn's disease (CD) and their relationship to clinical phenotypes. The clinical course of Crohn's disease is variable and relevant for treatment selection. Early aggressive treatment may change the course of disease but should be balanced by safety considerations. Currently, prediction of disease course is suboptimal. STUDY DESIGN:Colonic biopsies from CD colitis patients with different phenotypes were analyzed using histomorphometry. The quantitative results were used to predict postbiopsy clinical phenotypes and outcomes. Data analysis was performed using statistical and Neural Network models. RESULTS:Univariate analysis revealed differences between the phenotypes in the number of inflammatory cells (p = 0.003), lymphocytic aggregates (p = 0.005) and optical density of mature and young collagen (p = 0.008 and p = 0.01, respectively). Multivariate analysis allowed for differentiation between the clinical phenotypes and prediction of surgery, with good sensitivity and specificity. A neural network model predicted clinical phenotypes with an accuracy of 94%. CONCLUSIQN:.To our knowledge this is the first study that applied histomorphometry on early biopsies in order to predict the clinical phenotypes in Crohn's colitis. Measurements allowed differentiation and prediction of clinical phenotypes and outcomes such as surgery. This approach, in combination with other known predictors, may increase the ability to classify and predict the clinical course of CD colitis, thus improving patient management. Prospective validation using larger cohorts is needed.
    Development and Validation of an Interleukin-6 Nomogram to Predict Primary Non-response to Infliximab in Crohn's Disease Patients. Chen Yueying,Li Hanyang,Feng Qi,Shen Jun Frontiers in pharmacology The primary non-response (PNR) rate of infliximab (IFX) varies from 20 to 46% for the treatment of Crohn's disease (CD). Detected PNR reduces the improper use of specific treatments. To date, there is hardly any knowledge regarding early markers of PNR. The aim of this study was to evaluate the role of Interleukin-6 (IL-6) as an early predictor of PNR of IFX for the treatment of CD. We enrolled 322 bio-naïve patients diagnosed with CD from January 2016 to May 2020. Primary response was determined at week 14. Multivariable logistic regression was used to construct prediction models. Area under the curve (AUC), calibration and decision curve analyses (DCA) were assessed in the validation cohort. GEO data were analyzed to identify potential mechanisms of in IFX therapy for CD. PNR occurred in 31.06% (100 of 322) patients who were assessable at week 14. IL-6 levels significantly decreased after IFX therapy ( < 0.001). The validation model containing IL-6 presented enhanced discrimination with an AUC of 0.908 and high calibration. Decision curve analysis (DCA) indicated that the model added extra predictive value. GEO data confirmed the IL-6 levels were increased in the PNR group and IL-6-related differentially expressed genes (DEGs) were enriched in the inflammatory response. We concluded that IL-6 may be used as a predictive factor to assess the risk of PNR to IFX therapy. 10.3389/fphar.2021.654985
    Mucosal Profiles of Immune Molecules Related to T Helper and Regulatory T Cells Predict Future Relapse in Patients With Quiescent Ulcerative Colitis. Fukaura Keita,Iboshi Yoichiro,Ogino Haruei,Ihara Eikichi,Nakamura Kazuhiko,Nishihara Yuichiro,Nishioka Kei,Chinen Takatoshi,Iwasa Tsutomu,Aso Akira,Goto Ayako,Haraguchi Kazuhiro,Akiho Hirotada,Harada Naohiko,Ogawa Yoshihiro Inflammatory bowel diseases BACKGROUND:T helper (Th)- and regulatory T (Treg) cell-related immune molecules are implicated in ulcerative colitis (UC). However, the association between their mucosal expression during remission and the subsequent clinical course of UC is unknown. METHODS:The expression of cytokines and transcription factors related to Th1, Th2, Th17, and Treg in endoscopic mucosal biopsy specimens from 40 UC patients in clinical remission and 9 controls was measured by quantitative polymerase chain reaction. The relationship between their expression patterns, as stratified by Mayo Endoscopic Subscore (MES), and any future relapse was evaluated by univariate and multivariate analyses. RESULTS:Six of 40 patients (baseline MES 0/1/2, 22/14/4) experienced a relapse during the study period (median, 37 months). At baseline, even in the MES0 patients, the interleukin (IL)-17A of the patients was significantly upregulated in comparison with controls (P = 0.0351). Future relapse was associated with a higher baseline expression of IL-17A, IL-17F, and IL-21 in MES0/1, and the upregulation of IL-17F and IL-21 remained statistically significant when limited to MES0 patients. Kaplan-Meier analysis revealed that as a single marker, a higher IL-21 level best grouped patients with an increased risk of relapse (P = 0.0042). Furthermore, a multivariate model that consisted of IL-21 and T-bet showed an even greater value (P = 0.0001). CONCLUSIONS:The profiles of Th/Treg-related gene expression in the colonic mucosa are altered, even during clinical and endoscopic remission of UC, with a detectable Th17-predominant profile predicting future relapse. This association might represent latent immune dysregulation during disease quiescence and has the potential to be utilized to improve patient care. 10.1093/ibd/izy395
    A Novel Model for Predicting Incident Moderate to Severe Anemia and Iron Deficiency in Patients with Newly Diagnosed Ulcerative Colitis. Khan Nabeel,Patel Dhruvan,Shah Yash,Yang Yu-Xiao Digestive diseases and sciences BACKGROUND:Anemia and iron deficiency are common complications of ulcerative colitis (UC). We aimed to develop and internally validate a prediction model for the incidence of moderate to severe anemia and iron deficiency anemia (IDA) in newly diagnosed patients with UC. METHODS:Multivariable logistic regression was performed among a nationwide cohort of patients who were newly diagnosed with UC in the VA health-care system. Model development was performed in a random two-third of the total cohort and then validated in the remaining one-third of the cohort. As candidate predictors, we examined routinely available data at the time of UC diagnosis including demographics, medications, laboratory results, and endoscopy findings. RESULTS:A total of 789 patients met the inclusion criteria. For the outcome of moderate to severe anemia, age, albumin level and mild anemia at UC diagnosis were predictors selected for the model. The AUC for this model was 0.69 (95% CI 0.64-0.74). For the outcome of moderate to severe anemia with evidence of iron deficiency, the predictors included African-American ethnicity, mild anemia, age, and albumin level at UC diagnosis. The AUC was 0.76, (95% CI 0.69-0.82). Calibration was consistently good in all models (Hosmer-Lemeshow goodness of fit p > 0.05). The models performed similarly in the internal validation cohort. CONCLUSIONS:We developed and internally validated a prognostic model for predicting the risk of moderate to severe anemia and IDA among newly diagnosed patients with UC. This will help identify patients at high risk of these complications, who could benefit from surveillance and preventive measures. 10.1007/s10620-017-4512-3
    Improved risk prediction for Crohn's disease with a multi-locus approach. Kang Jia,Kugathasan Subra,Georges Michel,Zhao Hongyu,Cho Judy H, Human molecular genetics Genome-wide association studies have identified numerous loci demonstrating genome-wide significant association with Crohn's disease. However, when many single nucleotide polymorphisms (SNPs) have weak-to-moderate disease risks, genetic risk prediction models based only on those markers that pass the most stringent statistical significance testing threshold may be suboptimal. Haplotype-based predictive models may provide advantages over single-SNP approaches by facilitating detection of associations driven by cis-interactions among nearby SNPs. In addition, these approaches may be helpful in assaying non-genotyped, rare causal variants. In this study, we investigated the use of two-marker haplotypes for risk prediction in Crohn's disease and show that it leads to improved prediction accuracy compared with single-point analyses. With large numbers of predictors, traditional classification methods such as logistic regression and support vector machine approaches may be suboptimal. An alternative approach is to apply the risk-score method calculated as the number of risk haplotypes an individual carries, both within and across loci. We used the area under the curve (AUC) of the receiver operating curve to assess the performance of prediction models in large-scale genetic data, and observed that the prediction performance in the validation cohort continues to improve as thousands of haplotypes are included in the model, with the AUC reaching its plateau at 0.72 at ∼7000 haplotypes, and begins to gradually decline after that point. In contrast, using the SNP as predictors, we only obtained maximum AUC of 0.65. Validation studies in independent cohorts further support improved prediction capacity with multi-marker, as opposed to single marker analyses. 10.1093/hmg/ddr116
    Strategies for developing prediction models from genome-wide association studies. Wu Jincao,Pfeiffer Ruth M,Gail Mitchell H Genetic epidemiology Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with complex human diseases. However, risk prediction models based on them have limited discriminatory accuracy. It has been suggested that including many such SNPs can improve predictive performance. Here, we studied various aspects of model building to improve discriminatory accuracy, as measured by the area under the receiver operating characteristic curve (AUC), including: (1) How well does a one-phase procedure that selects SNPs and estimates odds ratios on the same data perform? (2) How should training data be allocated between SNP selection (Phase 1) and estimation (Phase 2) in a two-phase procedure? (3) Should SNP selection be based on P-value thresholding or ranking P-values? (4) How many SNPs should be selected? and (5) Is multivariate estimation preferred to univariate estimation in the presence of linkage disequilibrium (LD)? We used realistic estimates of the distributions of genetic effect sizes, allele frequencies, and LD patterns based on GWAS data for Crohn's disease and prostate cancer. Theory and simulations were used to estimate AUC. Empirical risk models based on 10,000 cases and controls had considerably lower AUC than theoretically achievable. The most critical aspect of prediction model building was initial SNP selection. The single-phase procedure achieved higher AUC than the two-phase procedure. Multivariate estimation did not perform as well as univariate (marginal) estimation. For complex diseases and samples of 10,000 or fewer cases and controls, one should limit the number of SNPs to tens or hundreds. 10.1002/gepi.21762
    Risk Matrix for Prediction of Disease Progression in a Referral Cohort of Patients with Crohn's Disease. Lakatos Peter L,Sipeki Nora,Kovacs Gyorgy,Palyu Eszter,Norman Gary L,Shums Zakera,Golovics Petra A,Lovasz Barbara D,Antal-Szalmas Peter,Papp Maria Journal of Crohn's & colitis BACKGROUND:Early identification of patients with Crohn's disease (CD) at risk of subsequent complications is essential for adapting the treatment strategy. We aimed to develop a prediction model including clinical and serological markers for assessing the probability of developing advanced disease in a prospective referral CD cohort. METHODS:Two hundred and seventy-one consecutive CD patients (42.4% males, median follow-up 108 months) were included and followed up prospectively. Anti-Saccharomyces cerevisiae antibodies (ASCA IgA/IgG) were determined by enzyme-linked immunosorbent assay. The final analysis was limited to patients with inflammatory disease behaviour at diagnosis. The final definition of advanced disease outcome was having intestinal resection or disease behaviour progression. RESULTS:Antibody (ASCA IgA and/or IgG) status, disease location and need for early azathioprine were included in a 3-, 5- and 7-year prediction matrix. The probability of advanced disease after 5 years varied from 6.2 to 55% depending on the combination of predictors. Similar findings were obtained in Kaplan-Meier analysis; the combination of ASCA, location and early use of azathioprine was associated with the probability of developing advanced disease (p < 0.001, log rank test). CONCLUSIONS:Our prediction models identified substantial differences in the probability of developing advanced disease in the early disease course of CD. Markers identified in this referral cohort were different from those previously published in a population-based cohort, suggesting that different prediction models should be used in the referral setting. 10.1093/ecco-jcc/jjv127
    Genetic Markers Predict Primary Nonresponse and Durable Response to Anti-Tumor Necrosis Factor Therapy in Ulcerative Colitis. Burke Kristin E,Khalili Hamed,Garber John J,Haritunians Talin,McGovern Dermot P B,Xavier Ramnik J,Ananthakrishnan Ashwin N Inflammatory bowel diseases Background:Despite a high nonresponse rate, predictors of response to anti-tumor necrosis factor (anti-TNF) therapy in ulcerative colitis (UC) remain limited. We aim to determine clinical and genetic predictors of primary nonresponse (PNR) and durable response (DR) to anti-TNF therapy in a large prospective UC cohort. Methods:Using the Illumina Immunochip, candidate polymorphisms associated with clinical outcomes of PNR and DR were separately evaluated and combined into weighted genetic risk scores. Combined genetic and clinical multivariable models for PNR and DR were compared with clinical predictive models using area under the receiver operating characteristic (AUROC) curves. Models were internally (DR) or externally (PNR) validated. Multivariable logistic regression was utilized to assess the association of genetic risk scores with infliximab levels and antibodies. Results:Of 231 patients, 28 (12%) experienced PNR and 120 (52%) experienced DR. There was no significant difference in clinical features between primary nonresponders and responders. Eight alleles were associated with PNR. A combined clinical-genetic model (AUROC, 0.87) more accurately predicted PNR compared with a clinical-only model (AUROC, 0.57; P < 0.0001). In an external cohort of 131 patients, increasing tertiles of PNR genetic risk score correlated with increased risk of PNR (P = 0.052). Twelve candidate loci were associated with DR. Genetic risk score quartiles for DR demonstrated a strong dose-response relationship in predicting treatment duration. Genetic risk scores for PNR and DR were not associated with infliximab levels or antibody formation. Conclusion:Genetic polymorphisms enhance prediction of PNR and DR to anti-TNF therapy in patients with UC. 10.1093/ibd/izy083
    Predictors of Early Failure After Fecal Microbiota Transplantation for the Therapy of Clostridium Difficile Infection: A Multicenter Study. Fischer Monika,Kao Dina,Mehta Shama R,Martin Tracey,Dimitry Joseph,Keshteli Ammar H,Cook Gwendolyn K,Phelps Emmalee,Sipe Brian W,Xu Huiping,Kelly Colleen R The American journal of gastroenterology OBJECTIVES:Fecal microbiota transplant (FMT) is a highly efficacious treatment for recurrent or refractory Clostridium difficile infection (CDI); however, 10-20% of patients fail to achieve cure after a single FMT. The aim of this study was to identify risk factors associated with FMT failure and to develop and validate a prediction model for FMT failure. METHODS:Patient characteristics, CDI history, FMT characteristics, and outcomes data for patients treated between 2011 and 2015 at three academic tertiary referral centers were prospectively collected. Early FMT failure was defined as non-response or recurrence of diarrhea associated with positive stool C. difficile toxin or PCR within 1 month of FMT. Late FMT failure was defined as recurrence of diarrhea associated with positive stool C. difficile toxin or PCR between 1 and 3 months of the FMT. Patient data from two centers were used to determine independent predictors of FMT failure and to build a prediction model. A risk index was constructed based on coefficients of final predictors. The patient cohort from the third center was used to validate the prediction model. RESULTS:Of 328 patients in the developmental cohort, 73.5% (N=241) were females with a mean age of 61.4±19.3 years; 19.2% (N=63) had inflammatory bowel disease (IBD), and 23.5% (N=77) were immunocompromised. The indication for FMT was recurrent CDI in 87.2% (N=286) and severe or severe-complicated in 12.8% (N=42). FMT was performed as an inpatient in 16.7% (N=54). The stool source was patient-directed donors in 40% (N=130) of cases. The early FMT failure rate was 18.6%, and the late failure rate was 2.7%. In the multivariable analysis, predictors of early FMT failure included severe or severe-complicated CDI (odds ratio (OR) 5.95, 95% confidence interval (CI): 2.26-15.62), inpatient status during FMT (OR 3.78, 95% CI: 1.55-9.24), and previous CDI-related hospitalization (OR 1.43, 95% CI: 1.18-1.75); with each additional hospitalization, the odds of failure increased by 43%. Risk scores ranged from 0 to 13, with 0 indicating low risk, 1-2 indicating moderate risk, and ≥3 indicating high risk. In the developmental cohort, early FMT failure rates were 5.6% for low risk, 12.7% for moderate risk, and 41% for high-risk patients. Of 134 patients in the validation cohort, 57% (N=77) were females with a mean age of 66±18.1 years; 9.7% (N=13) had IBD, and 17.9% (N=24) were immunocompromised. The early FMT failure rate at 1 month was 19.4%, with an additional 3% failing by 3 months. In the validation cohort, FMT failure rates were 2.1% for low risk, 16.1% for moderate risk, and 35.7% for high risk patients. The area under the receiver operating characteristic curve (AUROC) for FMT failure was 0.81 in the developmental cohort and 0.84 in the validation cohort. CONCLUSIONS:Severe and severe-complicated indication, inpatient status during FMT, and the number of previous CDI-related hospitalizations are strongly associated with early failure of a single FMT for CDI. The novel prediction model has good discriminative power at identifying individuals who are at high risk of failure after FMT therapy and may assist the treating physician in subsequent management plans. 10.1038/ajg.2016.180
    Development and Internal Validation of a Model Using Fecal Calprotectin in Combination with Infliximab Trough Levels to Predict Clinical Relapse in Crohn's Disease. Roblin Xavier,Duru Gerard,Williet Nicolas,Del Tedesco Emilie,Cuilleron Murielle,Jarlot Camille,Phelip Jean Marc,Boschetti Gilles,Flourié Bernard,Nancey Stephane,Peyrin-Biroulet Laurent,Paul Stephane Inflammatory bowel diseases BACKGROUND:The best noninvasive method predicting clinical relapse remains undetermined in infliximab (IFX)-treated patients with Crohn's disease. METHODS:All patients with CD on IFX maintenance treatment and in clinical remission for at least 16 weeks, between 2011 and 2014, were enrolled in a prospective single-center study. The Crohn's Disease Activity Index (CDAI), fecal calprotectin, C-reactive protein levels, antibodies (ATI), and trough level (TLI) of IFX were measured at every IFX infusion. The best thresholds of TLI (2 versus 3 μg/mL) and calprotectin (50 versus 250 μg/g stools) were identified across four logistic regression models. RESULTS:One hundred nineteen patients (mean age: 34 ± 12 yrs, mean disease duration: 7.8 yrs) were included. Mean follow-up was 20.4 months, and 17% of the patients were on IFX and azathioprine at inclusion. During follow-up, 37 patients (31.1%) relapsed, 78% within the first 6 months. The clinical characteristics of the relapsed and nonrelapsed patients were similar. After logistic regression, fecal calprotectin >250 μg/g stools (OR: 4.09; 95% CI, 1.01-16.21; P = 0.049) and TLI <2 μg/mL (OR: 14.85; 95% CI, 3.67-60; P < 0.0001) were associated with loss of response. A training cohort of 55 patients was isolated randomly to implement prediction rules for loss of response. The best predictive rules were the combination of a TLI <2 μg/mL and a fecal calprotectin level >250 μg/g stools (78.3%). These rules were validated on a test cohort of 64 patients with an accuracy of 87%, (sensitivity = 0.94, specificity = 0.84, positive predictive value = 0.73, and negative predictive value = 0.97). CONCLUSIONS:In IFX-treated patients with CD in clinical remission, a combination of TLI (<2 μg/mL) and fecal calprotectin (>250 μg/g of stools) is a good model for predicting loss of response. In contrast with previous data, low TLIs ranging from 2 to 3 μg/mL should neither systematically lead to the optimization of IFX use nor a switch in the treatment. 10.1097/MIB.0000000000000986
    Predictive model for the outcome of infliximab therapy in Crohn's disease based on apoptotic pharmacogenetic index and clinical predictors. Hlavaty Tibor,Ferrante Marc,Henckaerts Liesbet,Pierik Marie,Rutgeerts Paul,Vermeire Severine Inflammatory bowel diseases BACKGROUND:Infliximab (IFX) is an effective therapy for refractory luminal and fistulizing Crohn's disease (CD). Predictors of response could improve selection of patients with a higher probability of favorable outcomes and could improve the safety profile. We aimed to develop a predictive model for the response to infliximab in CD. METHODS:Genetic and clinical data collected in a previous pharmacogenetic study of apoptosis genes were analyzed using SAS Enterprise miner modeling software and SPSS 12.0. We proposed a novel apoptotic pharmacogenetic index (API) with a score ranging from 0 (low apoptotic response) to 3 (high apoptotic response) and subsequently developed a decision tree model. RESULTS:Response and remission rates significantly increased with API score (P = 0.005 in the group of patients with luminal CD, P = 0.02 in the group of patients with fistulizing CD). Patients with an API < or = 1 (n = 59) had the lowest response and remission rates in both the luminal CD (50% and 39.5%, respectively) and fistulizing CD (61.9% and 28.6%, respectively) groups, compared to those with an API of 2 (n = 158), whose response and remission rates were 73.8% and 56.1%, respectively, in the luminal CD group and 85.7% and 44.9%, respectively, in the fistulizing CD group; and those with an API of 3 (n = 10), whose response and remission rates were 100% and 85.7%, respectively, in the luminal CD group and 100% and 0% in the fistulizing CD group. Response in patients with an API < or = 1 was significantly influenced by concurrent azathioprine therapy in the luminal CD (21.4% versus 78.9%, P < 0.001) and in the fistulizing CD (46.6% versus 100%, P = 0.04) groups. In patients with an API of 2, we saw an interaction with age older than 40 years and location of disease (response 52.2% versus 83.9%, P = 0.008) in the luminal CD group and with baseline CRP greater than 5 mg/L (73.9% versus 93.9%, P = 0.04) in the fistulizing CD group. CONCLUSIONS:From our newly proposed apoptotic pharmacogenetic index and clinical predictors, we developed a model for prediction of low, medium, and high responses to the first infusion of IFX in patients with CD. Further studies are needed to confirm the hypothesis generated by our study. 10.1002/ibd.20024
    Early histological findings may predict the clinical phenotype in Crohn's colitis. Klein Amir,Mazor Yoav,Karban Amir,Ben-Itzhak Ofer,Chowers Yehuda,Sabo Edmond United European gastroenterology journal BACKGROUND AND AIMS:Predicting the clinical course of Crohn's disease (CD) is relevant for treatment selection. Currently, such diagnostic tools are lacking. In a previous pilot study, morphometric tissue image analysis showed promise in predicting the clinical phenotype and need for surgery. In this study, we aimed to validate our previous results on a larger cohort. METHODS:Colonic biopsies from CD patients with colonic or ileocolonic disease and at least five years of post-biopsy clinical follow-up were analyzed. The results were used to predict post-biopsy clinical phenotypes and outcomes. Data analysis was performed using multivariate regression models, discriminant score (DS) computations and Neural Network (NNET). RESULTS:Multivariate analysis of morphometric variables differentiated between B1 and B2 phenotypes (sensitivity 81%, specificity 74%, accuracy on cross-validation 75%; area under the curve (AUC) of 0.74 (CI 0.6-0.84; NNET model sensitivity 87%, specificity 67% on the testing population)). Differentiation between B1 and B3 phenotypes was also possible (sensitivity 69%, specificity 76%, accuracy 70.5% on cross-validation; AUC 0.78 (CI 0.68-0.89); NNET model sensitivity 78%, specificity 77% on the testing population)). Differentiating between B2 and B3 phenotypes was not possible using morphometric variables. Multivariate analysis predicted surgery (sensitivity 67%, specificity 72.5%, accuracy 69%; AUC 0.72 (CI 0.61-0.82); NNET model sensitivity 80%, specificity 91% on the testing population)). CONCLUSIONS:This study validates previous results and suggests that morphometric image analysis of early biopsies from Crohn's colitis patients may contribute to the prediction of future outcomes such as clinical phenotype and surgery. Prospective validation on larger cohorts is still needed. 10.1177/2050640616676435
    A Novel Predictive Nomogram for Early Endoscopic Recurrence after Intestinal Resection for Crohn's Disease. Ikeda Atsuyo,Miyoshi Norikatsu,Fujino Shiki,Iijima Hideki,Takahashi Hidekazu,Haraguchi Naotsugu,Nishimura Junichi,Hata Taishi,Matsuda Chu,Doki Yuichiro,Mori Masaki,Mizushima Tsunekazu Digestion BACKGROUND/AIMS:Endoscopic recurrence (ER) after intestinal resection for Crohn's disease (CD) precedes the clinical recurrence, and the severity of ER correlates with the severity of the subsequent clinical recurrence. This study aimed to identify risk factors related to early ER after intestinal resection for CD and to create a prediction model. METHODS:The patients who underwent intestinal resection for CD between April 2008 and April 2017 and took endoscopic evaluation between 6 and 12 months after surgery were retrospectively analyzed. RESULTS:A total of 15 out of 52 (29%) patients developed early ER. A univariate analysis demonstrated that early ER was significantly correlated with history of prior intestinal resections for CD (p = 0.005), low preoperative albumin levels (p = 0.035), and excessive perioperative inflammation (i.e., high C-reactive protein levels in both preoperative and postoperative periods; p = 0.034). Based on these clinical factors, a nomogram for predicting early ER was created with the area under the curve 0.808. CONCLUSION:We developed a novel predictive nomogram for early ER after intestinal resection for CD. This prediction model might assist clinicians in managing patients with CD after an intestinal resection. Additional validation studies are currently being developed. 10.1159/000495981
    Diagnostic Accuracy of Fecal Calprotectin Concentration in Evaluating Therapeutic Outcomes of Patients With Ulcerative Colitis. Stevens Toer W,Gecse Krisztina,Turner Jerrold R,de Hertogh Gert,Rubin David T,D'Haens Geert R Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:Histologic features of inflammation (histologic inflammation) are associated with clinical relapse in patients with ulcerative colitis (UC). Concentration of fecal calprotectin (FC) can be used to identify patients with mucosal inflammation. We aimed to assess the accuracy of FC measurements in identifying patients with histologic inflammation and to develop a model to predict outcomes of therapy. METHODS:We performed a post hoc analysis of data from a phase 4 trial of the efficacy of multimatrix mesalamine in patients with mild to moderate UC (the MOMENTUM trial). We obtained clinical, endoscopic, and histologic data from week 8 (n = 639) and week 52 (n = 373) of the trial. We used area under the receiver operating characteristic curves to determine the accuracy and optimal cut-off values of FC in identifying patients with different therapeutic outcomes (clinical remission, endoscopic healing, deep remission, or histologic remission) at week 8 and week 52. We performed multivariable logistic regression analyses to identify factors associated with these outcomes. RESULTS:Median FC concentrations were lower in patients who achieved outcomes of clinical remission, endoscopic healing, deep remission, or histologic remission vs patients who did not. FC concentrations identified patients with endoscopic healing and histologic remission with area under the receiver operating characteristic curve values of 0.77 and 0.76 at week 8, and 0.79 and 0.80 at week 52, respectively. The optimal FC cut-off concentrations for identification of patients with histologic remission were 75 μg/g at week 8 and 99 μg/g at week 52. In the subpopulation with an endoscopy score of 0, median FC concentrations were lower in patients with histologic remission than in patients with microscopic inflammation at week 8 (30 vs 140 μg/g; area under the receiver operating characteristic, 0.72) and week 52 (21.5 vs 134.5 μg/g; area under the receiver operating characteristic, 0.71). At both time points, the optimal FC cut-off concentration was approximately 75 μg/g. Our final prediction model for week 52 histologic remission comprised endoscopic score at week 8, FC concentration at week 8, and histologic activity at baseline and week 8. CONCLUSIONS:A post hoc analysis of data from a phase 4 trial found that, even in patients with complete endoscopic healing of UC, FC concentration can be used to discriminate patients with ongoing microscopic inflammation from patients with histologic remission. The optimal cut-off concentration of FC is between 75 and 100 μg/g. ClinicalTrials.gov no: NCT01124149. 10.1016/j.cgh.2020.08.019
    Faecal Microbiota Transplantation Reduces Susceptibility to Epithelial Injury and Modulates Tryptophan Metabolism of the Microbial Community in a Piglet Model. Geng Shijie,Cheng Saisai,Li Yuan,Wen Zhengshun,Ma Xin,Jiang Xuemei,Wang Yizhen,Han Xinyan Journal of Crohn's & colitis Background and Aims:Faecal microbiota transplantation [FMT] has shown promise as a treatment for inflammatory bowel disease [IBD]. Using a piglet model, our previous study indicated that exogenous faecal microbiota can increase the expressions of tight junction proteins, mucin and antimicrobial peptide in the intestinal mucosa, suggesting a beneficial effect of FMT on gut barrier and gastrointestinal health. However, specific connections between FMT-induced microbial changes and modulation of the intestinal barrier remain to be fully illustrated. Here, we aimed to determine the potential role of metabolic function of gut microbiota in the beneficial effects of FMT. Methods:The influence of FMT on the maintenance of intestinal homeostasis was assessed by early-life gut microbiota intervention on newborn piglets and subsequent lipopolysaccharide [LPS] challenge. Analysis of the gut microbiome and metabolome was carried out by 16S rRNA gene sequencing and multiple mass spectrometry platforms. Results:FMT modulated the diversity and composition of colonic microbiota and reduced the susceptibility to LPS-induced destruction of epithelial integrity and severe inflammatory response. Metabolomic analysis revealed functional changes of the gut metabolome along with a significant increase of the typical microbiota-derived tryptophan catabolite indole-3-acetic acid in the colonic lumen. In concordance with the metabolome data, metagenomics prediction analysis based on 16S rRNA gene sequencing also demonstrated that FMT modulated the metabolic functions of gut microbiota associated with indole alkaloid biosynthesis, cytochrome P450 and intestinal homeostasis, which coincided with up-regulation of cytokine interleukin-22 and enhanced activation of aryl hydrocarbon receptor in the recipient colon. Conclusions:Our data reveal a regulatory effect of FMT on tryptophan metabolism of gut microbiota in the recipient colon, which may play a potential role in maintenance of the intestinal barrier. 10.1093/ecco-jcc/jjy103
    Development of a clinical model to predict secondary non-response of infliximab treatment in Crohn's disease. Xu Lijun,Shen Jun,Zheng Qing International journal of colorectal disease PURPOSE:Secondary non-response to infliximab (IFX) in patients with Crohn's disease (CD) is so common that prediction of non-response is required to adopt the optimal therapy for an individual patient. METHODS:The clinical model was constructed in a training cohort. Clinical features, serological parameters, and genetic biomarkers at week 14 IFX therapy were obtained as predictors. Secondary non-response was defined at week 54. Univariate analysis was first performed to eliminate irrelevant predictors with non-response. Then, a logistic regression model was developed by using predictors with P < 0.1 in a univariate analysis. Finally, the model was validated with reference to its discrimination, calibration, and decision curve analysis (DCA). RESULTS:In a univariate analysis, erythrocyte sedimentation rate (ESR), the previous surgery, disease location, C-reactive protein (CRP), and TNFRSF1B (676 T>G) were found associated with secondary non-response to IFX. Logistic regression analysis with stepwise backward selection P < 0.05 then identified that ESR, the previous surgery, CRP, and TNFRSF1B (676 T>G) could serve as independent predictors, and a clinical model was developed based on the above predictors. Model 2 with TNFRSF1B (676 T>G) incorporated demonstrated more satisfactory discrimination (P = 0.029), better calibration (U P2 > 0.05), and higher clinical value in the validation cohort. CONCLUSIONS:The study presents a model to predict non-response to IFX in CD, which incorporates previous surgery, ESR, CRP, and TNFRSF1B (676 T>G). This model can be used to help clinicians adjust the therapeutic strategy and CD patients avoid unnecessary exposure to IFX. 10.1007/s00384-020-03679-8
    Systematic Review and External Validation of Prediction Models Based on Symptoms and Biomarkers for Identifying Endoscopic Activity in Crohn's Disease. Brand Eelco C,Elias Sjoerd G,Minderhoud Itta M,van der Veen Julius J,Baert Filip J,Laharie David,Bossuyt Peter,Bouhnik Yoram,Buisson Anthony,Lambrecht Guy,Louis Edouard,Pariente Benjamin,Pierik Marieke J,van der Woude C Janneke,D'Haens Geert R A M,Vermeire Séverine,Oldenburg Bas, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:Endoscopic healing, an important target of treatment for Crohn's disease (CD), requires ileocolonoscopy, which is costly and burdensome. We investigated whether published noninvasive models (based on symptoms and biomarkers) to evaluate CD activity have sufficient accuracy to replace ileocolonoscopy. METHODS:We performed a systematic review of published noninvasive diagnostic models to evaluate CD activity that used endoscopic features of activity (endoscopic activity) or healing as the reference standard. We externally validated these models for the outcome endoscopic activity (CD endoscopic index of severity scores, ≥3) using data from the a randomized controlled trial investigating tailored treatment with infliximab for active luminal Crohn's disease (TAILORIX) study (346 ileocolonoscopies in 155 patients) and the Utrecht Activity Index (UAI) study (93 ileocolonoscopies in 82 patients). We calculated the area under the receiver operating characteristic curves (AUROCs) for the models using data from these studies, and compared the performance of these models against measurements of fecal calprotectin (FC) and C-reactive protein (CRP). RESULTS:We screened 5303 articles and identified 27 models (from 21 studies) for our analysis. Seven models could be validated externally; in the TAILORIX data set, these models identified patients with endoscopic activity with AUROC values ranging from 0.61 (95% CI, 0.51-0.70) to 0.81 (95% CI, 0.76-0.86). In this data set, the AUROC value for FC concentration was 0.79 (95% CI, 0.74-0.85) and the AUROC value for CRP level was 0.72 (95% CI, 0.66-0.77). The AUROC values for the validation in the UAI data set were similar. In the TAILORIX and/or UAI data set, 4 of the 7 models, as well as the FC and CRP assays, were able to identify patients with endoscopic activity with positive predictive values of 90% or more. Two of the 7 models (but not the FC or CRP values) identified patients without endoscopic activity with a negative predictive value (NPV) of 90% or more, leading to correct prediction of endoscopic healing in 3.2% to 11.3% of all patients. For example, applying the Herranz-Bachiller model (1 of 7 models) at a NPV of 92.1% and a positive predictive value of 91.9% correctly identified 35.7% of all patients in whom ileocolonoscopy could be avoided for expected endoscopic activity or healing but incorrectly identified 3.2% of all patients. Most ileocolonoscopies (66.5% in TAILORIX and 72.6% in the UAI of all ileocolonoscopies) could be avoided correctly based on concentrations of FC of 100 μg/g or less and 250 μg/g or higher. However, using this range of FC concentrations to identify patients who do not require ileocolonoscopy caused 18.7% of all patients in the TAILORIX cohort and 19.8% of all patients in the UAI cohort to be predicted incorrectly to have endoscopic activity or healing. CONCLUSIONS:In a systematic review and external validation of noninvasive models to identify patients with endoscopic activity of CD, we found only 2 of 7 models evaluated to have NPVs of 90% or more, however, leading to correctly predicted EH in only a small proportion of patients. Ileocolonoscopy therefore remains the mainstay to evaluate CD mucosal disease activity and healing. 10.1016/j.cgh.2019.12.014
    Development and validation of risk prediction algorithm (QThrombosis) to estimate future risk of venous thromboembolism: prospective cohort study. Hippisley-Cox Julia,Coupland Carol BMJ (Clinical research ed.) OBJECTIVES:To derive and validate a new clinical risk prediction algorithm (QThrombosis, www.qthrombosis.org) to estimate individual patients' risk of venous thromboembolism. DESIGN:Prospective open cohort study using routinely collected data from general practices. Cox proportional hazards models used in derivation cohort to derive risk equations evaluated at 1 and 5 years. Measures of calibration and discrimination undertaken in validation cohort. SETTING:564 general practices in England and Wales contributing to the QResearch database. PARTICIPANTS:Patients aged 25-84 years, with no record of pregnancy in the preceding 12 months or any previous venous thromboembolism, and not prescribed oral anticoagulation at baseline: 2,314,701 in derivation cohort and 1,240,602 in validation cohort. Outcomes Incident cases of venous thromboembolism, either deep vein thrombosis or pulmonary embolism, recorded in primary care records or linked cause of death records. RESULTS:The derivation cohort included 14,756 incident cases of venous thromboembolism from 10,095,199 person years of observation (rate of 14.6 per 10,000 person years). The validation cohort included 6913 incident cases from 4,632,694 person years of observation (14.9 per 10,000 person years). Independent predictors included in the final model for men and women were age, body mass index, smoking status, varicose veins, congestive cardiac failure, chronic renal disease, cancer, chronic obstructive pulmonary disease, inflammatory bowel disease, hospital admission in past six months, and current prescriptions for antipsychotic drugs. We also included oral contraceptives, tamoxifen, and hormone replacement therapy in the final model for women. The risk prediction equation explained 33% of the variation in women and 34% in men in the validation cohort evaluated at 5 years The D statistic was 1.43 for women and 1.45 for men. The receiver operating curve statistic was 0.75 for both sexes. The model was well calibrated. CONCLUSIONS:We have developed and validated a new risk prediction model that quantifies absolute risk of thrombosis at 1 and 5 years. It can help identify patients at high risk of venous thromboembolism for prevention. The algorithm is based on simple clinical variables which the patient is likely to know or which are routinely recorded in general practice records. The algorithm could be integrated into general practice clinical computer systems and used to risk assess patients before hospital admission or starting medication which might increase the risk of venous thromboembolism. 10.1136/bmj.d4656
    Development of a Novel Predictive Model for the Clinical Course of Crohn's Disease: Results from the CONNECT Study. Park Yehyun,Cheon Jae Hee,Park Yi Lang,Ye Byong Duk,Kim You Sun,Han Dong Soo,Kim Joo Sung,Hong Sung Noh,Kim Young Ho,Jeon Seong Ran,Kim Won Ho, Inflammatory bowel diseases BACKGROUND:A considerable number of patients with Crohn's disease (CD) develop irreversible intestinal damage, although the early administration of immunomodulatory or biological therapies might prevent this. The aims of our study were to develop and validate a novel predictive model that can be used to predict the risk of surgical intervention in Korean patients with CD. METHODS:The prognostic model was derived from the multicenter longitudinal CONNECT (CrOhn's disease cliNical NEtwork and CohorT) study cohort consisting of 1338 patients with CD, who were split into training and validation sets. The Korean Crohn's Disease Prediction (KCDP) model was developed with the training set data using the Cox proportional hazards model and multivariate analysis, and was then validated using the validation set. RESULTS:A total of 1271 patients with CD were analyzed. During the follow-up period of 10,188 patient-years (median 7.1 yrs), 361 patients (28.4%) underwent CD-related surgery. Age at diagnosis, jejunal involvement, initial disease behavior, and perianal disease at diagnosis were associated with a poor prognosis and included in the KCDP model, which showed a modest discrimination ability with a Harrel's c-index of 0.731 at 5 years, and was well calibrated (Hosmer-Lemeshow χ = 8.230, P = 0.511). CONCLUSIONS:This is the first validated surgery risk prediction model for Korean patients with CD; it provides accurate individualized estimates of the probability of surgery using clinical parameters collected at diagnosis. This model might guide appropriate patient selection for the early intensive treatment of CD. 10.1097/MIB.0000000000001106
    Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort. Weersma R K,Stokkers P C F,van Bodegraven A A,van Hogezand R A,Verspaget H W,de Jong D J,van der Woude C J,Oldenburg B,Linskens R K,Festen E A M,van der Steege G,Hommes D W,Crusius J B A,Wijmenga C,Nolte I M,Dijkstra G, Gut BACKGROUND:Crohn's disease and ulcerative colitis have a complex genetic background. We assessed the risk for both the development and severity of the disease by combining information from genetic variants associated with inflammatory bowel disease (IBD). METHODS:We studied 2804 patients (1684 with Crohn's disease and 1120 with ulcerative colitis) and 1350 controls from seven university hospitals. Details of the phenotype were available for 1600 patients with Crohn's disease and for 800 with ulcerative colitis. Genetic association for disease susceptibility was tested for the nucleotide-binding and oligomerisation domain 2 gene (NOD2), the IBD5 locus, the Drosophila discs large homologue 5 and autophagy-related 16-like 1 genes (DLG5 and ATG16L1) and the interleukin 23 receptor gene (IL23R). Interaction analysis was performed for Crohn's disease using the most associated single nucleotide polymorphism (SNP) for each locus. Odds ratios were calculated in an ordinal regression analysis with the number of risk alleles as an independent variable to analyse disease development and severity. RESULTS:Association with Crohn's disease was confirmed for NOD2, IBD5, DLG5, ATG16L1 and IL23R. Patients with Crohn's disease carry more risk alleles than controls (p = 3.85 x 10(-22)). Individuals carrying an increasing number of risk alleles have an increasing risk for Crohn's disease, consistent with an independent effects multiplicative model (trend analysis p = 4.25 x 10(-23)). Patients with Crohn's disease with a more severe disease course, operations or an age of onset below 40 years have more risk alleles compared to non-stricturing, non-penetrating behaviour (p = 0.0008), no operations (p = 0.02) or age of onset above 40 years (p = 0.028). CONCLUSION:Crohn's disease is a multigenic disorder. An increase in the number of risk alleles is associated with an increased risk for the development of Crohn's disease and with a more severe disease course. Combining information from the known common risk polymorphisms may enable clinicians to predict the course of Crohn's disease. 10.1136/gut.2007.144865
    Risk matrix for prediction of advanced disease in a population-based study of patients with Crohn's Disease (the IBSEN Study). Solberg Inger C,Cvancarova Milada,Vatn Morten H,Moum Bjørn, Inflammatory bowel diseases BACKGROUND:Identifying patients with Crohn's disease with increased risk of subsequent complications is essential for appropriate treatment. Based on exploratory analysis, we developed a prediction model for assessing the probability of developing advanced disease 5 and 10 years after diagnosis. METHODS:A population-based cohort of 237 patients with Crohn's disease diagnosed from 1990-1994 was followed for 10 years. In the 5-year analysis, advanced disease was defined as having intestinal resection, progression in disease behavior, or need for thiopurines. The analysis was limited to patients with uncomplicated disease at diagnosis who were alive (n = 140), excluding those who were lost during follow-up (n = 8). For the 10-year analysis, advanced disease was defined as having surgery, excluding those who had surgery within the first 30 days (n = 7), those who died (n = 18), or were lost during follow-up (n = 22). Based on the best fitted multiple model, the probabilities of advanced disease were computed for selected baseline levels of the covariates and the results were arranged in a prediction matrix. Except for ASCA, all predictors were measured at diagnosis. RESULTS:ASCA status, disease location, age, and need for systemic steroids were included in the 5-year prediction matrix. The probabilities of advanced disease during this period varied from 8.6% to 92.0% depending on the combination of predictors. The 10-year matrix combined ASCA status, disease behavior, age, and need for systemic steroids; the probabilities of advanced disease ranged from 12.4% to 96.7%. CONCLUSIONS:Our prediction models revealed substantial differences in the probability of developing advanced disease in the short and intermediate course of Crohn's disease, suggesting that a model-based prediction matrix is useful in early disease management. 10.1097/01.MIB.0000436956.78220.67
    Upper Gastrointestinal Tract Involvement in Crohn's Disease: Frequency, Risk Factors, and Disease Course. Greuter Thomas,Piller Alberto,Fournier Nicolas,Safroneeva Ekaterina,Straumann Alex,Biedermann Luc,Godat Sébastien,Nydegger Andreas,Scharl Michael,Rogler Gerhard,Vavricka Stephan R,Schoepfer Alain M, Journal of Crohn's & colitis Background:The frequency of upper gastrointestinal [GI] tract involvement in Crohn`s disease [CD] has been reported with a large variation. Risk factors and disease course of patients with upper GI tract involvement remain largely elusive. Methods:Data on CD patients in the Swiss Inflammatory Bowel Disease Cohort were analysed. Patients with upper GI tract involvement were compared with controls. Logistic regression models for prediction of upper GI tract involvement and Cox proportional hazard models for occurrence of complications were computed. Results:We included 1638 CD patients, of whom 107 [6.5%] presented with upper GI tract involvement at the time of diagnosis and 214 [13.1%] at any time. Prevalence of such involvement at diagnosis increased over time [5.1% for 1955-95 versus 11.3% for 2009-16]. In a multivariate logistic regression model, male sex and diagnosis between 2009 and 2016 [versus before 1995] were independent predictors for presence of upper GI tract involvement at CD diagnosis (odds ratio [OR] 1.600, p = 0.021 and OR 2.686, p < 0.001, respectively), whereas adult age was a negative predictor [OR 0.388, p = 0.001]. Patients with upper GI tract involvement showed a disease course similar to control patients (hazard ratio [HR] for any complications 0.887, (95% confidence interval [CI] 0.409-1.920), and a trend towards occurrence of fewer intestinal fistulas [log-rank test p = 0.054]. Conclusions:Prevalence of upper GI tract involvement has been increasing over the past decades. Male sex and young age at diagnosis were identified as the main predictive factors for such involvement at CD diagnosis. Involvement of upper GI tract did not result in a worse outcome. 10.1093/ecco-jcc/jjy121
    Serum calprotectin as a biomarker for Crohn's disease. Meuwis M-A,Vernier-Massouille G,Grimaud J C,Bouhnik Y,Laharie D,Piver E,Seidel L,Colombel J F,Louis E, Journal of Crohn's & colitis BACKGROUND AND AIMS:In Crohn's disease, correlation between clinical assessment and disease activity at tissue level is weak. Our aim was to evaluate the value of serum calprotectin as a biomarker for Crohn's disease. METHODS:The STORI trial patients (n=115) were studied at baseline, in clinical remission before infliximab withdrawal, or at the time of relapse after infliximab withdrawal. Forty healthy controls were also studied. Serum calprotectin level was measured by ELISA. Data were analyzed through correlation analyses, Kaplan Meier curves and Cox model, using available Crohn's Disease Activity Index (CDAI), Crohn's Disease Endoscopic Index of Severity (CDEIS), fecal calprotectin and C-reactive protein levels (hsCRP). RESULTS:Median serum calprotectin was 8892 ng/mL (range: 410-125,000 ng/mL) in Crohn disease patients as compared with 1318 ng/mL (range: 215.8-3770 ng/mL) in controls (P<0.0001). Serum calprotectin was significantly higher for active disease (median=19,584 ng/mL) than for inactive disease (median=8353 ng/mL) (P<0.0001). Serum calprotectin correlated with hsCRP (r=0.4092, P<0.0001) and CDAI (r=0.4442, P<0.0001), but not with CDEIS, on the contrary to fecal calprotectin (r=0.6458, 0.5515, 0.2577 with P<0.0001, P<0.0001, P=0.019 respectively). In multivariate analysis, serum calprotectin used as a discrete variable (threshold: 5675 ng/ml), appeared complementary to hsCRP (>5 mg/l) and fecal calprotectin (>250 μg/g) to predict relapse after infliximab withdrawal (P=0.0173, 0.0024 and 0.0002; HR: 3.191, 3.561 and 4.120). CONCLUSIONS:As a CD biomarker, serum calprotectin has a similar profile as hsCRP. It is also complementary to fecal calprotectin and hsCRP for prediction of relapse after infliximab withdrawal. 10.1016/j.crohns.2013.06.008
    The Use of Readily Available Longitudinal Data to Predict the Likelihood of Surgery in Crohn Disease. Stidham Ryan W,Liu Yumu,Enchakalody Binu,Van Tony,Krishnamurthy Venkataramu,Su Grace L,Zhu Ji,Waljee Akbar K Inflammatory bowel diseases BACKGROUND:Although imaging, endoscopy, and inflammatory biomarkers are associated with future Crohn disease (CD) outcomes, common laboratory studies may also provide prognostic opportunities. We evaluated machine learning models incorporating routinely collected laboratory studies to predict surgical outcomes in U.S. Veterans with CD. METHODS:Adults with CD from a Veterans Health Administration, Veterans Integrated Service Networks (VISN) 10 cohort examined between 2001 and 2015 were used for analysis. Patient demographics, medication use, and longitudinal laboratory values were used to model future surgical outcomes within 1 year. Specifically, data at the time of prediction combined with historical laboratory data characteristics, described as slope, distribution statistics, fluctuation, and linear trend of laboratory values, were considered and principal component analysis transformations were performed to reduce the dimensionality. Lasso regularized logistic regression was used to select features and construct prediction models, with performance assessed by area under the receiver operating characteristic using 10-fold cross-validation. RESULTS:We included 4950 observations from 2809 unique patients, among whom 256 had surgery, for modeling. Our optimized model achieved a mean area under the receiver operating characteristic of 0.78 (SD, 0.002). Anti-tumor necrosis factor use was associated with a lower probability of surgery within 1 year and was the most influential predictor in the model, and corticosteroid use was associated with a higher probability of surgery. Among the laboratory variables, high platelet counts, high mean cell hemoglobin concentrations, low albumin levels, and low blood urea nitrogen values were identified as having an elevated influence and association with future surgery. CONCLUSIONS:Using machine learning methods that incorporate current and historical data can predict the future risk of CD surgery. 10.1093/ibd/izab035
    The establishment of a regression model from four modes of ultrasound to predict the activity of Crohn's disease. Jing Jigang,Wu Yuting,Zhang Hu,Zhang Yan,Mu Jingxi,Luo Yan,Zhuang Hua Scientific reports To establish a multi-parametric regression model from four modes of ultrasound to predict the activity of Crohn's disease (CD) noninvasively. Score of 150 of the Crohn's Disease Activity Index (CDAI) was taken as the cut-off value to divide the involved bowel segments of 51 patients into the active and inactive group. Eleven parameters from four modes of ultrasound (B-mode ultrasonography, color Doppler flow imaging, contrast-enhanced ultrasonography and shear wave elastography) were compared between the two groups to investigate the relationship between multimodal ultrasonic features and CD activity. P < 0.05 was considered statistically significant. Parameters with AUC larger than 0.5 was selected to establish the prediction model of CDAI. Totally seven ultrasound parameters (bowel wall thickness, mesenteric fat thickness, peristalsis, texture of enhancement, Limberg grade, bowel wall perforation and bowel wall stratification) were significantly different between active and inactive group. A regression model was established based on the seven parameters as followed: CDAI = 211.325 + 3.186BWT - 53.003BWS + 6.280BWP + 0.392MFT + 22.239PS + 79.012LG + 72.793TE. (R = 0.72, P = 0.037). The multimodal ultrasound parametric regression model was designed to predict CDAI score invasively. The model has the potential to provide an alternative method for quantifying the CD activity. 10.1038/s41598-020-79944-1
    Parameters of a severe disease course in ulcerative colitis. Stallmach Andreas,Nickel Luisa,Lehmann Thomas,Bokemeyer Bernd,Bürger Martin,Hüppe Dietrich,Kruis Wolfgang,Nikolaus Susanna,Preiss Jan C,Sturm Andreas,Teich Niels,Schmidt Carsten World journal of gastroenterology AIM:To detect high risk patients with a progressive disease course of ulcerative colitis (UC) requiring immunosuppressive therapy (IT). METHODS:A retrospective, multicenter analysis of 262 UC patients from eight German tertiary inflammatory bowel disease centres was performed. Patients were divided into two groups depending on the patients need to initiate immunosuppressive therapy in the disease course. A comparison between the two groups was made with regard to demographics, clinical and laboratory parameters obtained within three months after UC diagnosis and the response to first medical therapy. Using this data, a prognostic model was established to predict the individual patients probability of requiring an immunosuppressive therapy. RESULTS:In 104 (39.7%) out of 262 patients, UC therapy required an immunosuppressive treatment. Patients in this group were significantly younger at time of diagnosis (HR = 0.981 ± 0.014 per year, P = 0.009), and required significantly more often a hospitalisation (HR = 2.5 ± 1.0, P < 0.001) and a systemic corticosteroid therapy at disease onset (HR = 2.4 ± 0.8, P < 0.001), respectively. Response to steroid treatment was significantly different between the two groups of patients (HR = 5.2 ± 3.9 to 50.8 ± 35.6 compared to no steroids, P = 0.016 to P < 0.001). Furthermore, in the IT group an extended disease (HR = 3.5 ± 2.4 to 6.1 ± 4.0 compared to proctitis, P = 0.007 to P = 0.001), anemia (HR = 2.2 ± 0.8, P < 0.001), thrombocytosis (HR = 1.9 ± 1.8, P = 0.009), elevated C-reactive protein (CRP) (HR = 2.1 ± 0.9, P < 0.001), and extraintestinal manifestations in the course of disease (HR = 2.6 ± 1.1, P = 0.004) were observed. Six simple clinical items were used to establish a prognostic model to predict the individual risk requiring an IT. This probability ranges from less than 2% up to 100% after 5 years. Using this, the necessity of an immunosuppressive therapy can be predicted in 60% of patients. Our model can determine the need for an immunosuppressive drug therapy or if a "watch and wait" approach is reasonable already early in the treatment course of UC. CONCLUSION:Using six simple clinical parameters, we can estimate the patients individual risk of developing a progressive disease course. 10.3748/wjg.v20.i35.12574
    The fecal hemoglobin concentration, age and sex test score: Development and external validation of a simple prediction tool for colorectal cancer detection in symptomatic patients. Cubiella Joaquín,Digby Jayne,Rodríguez-Alonso Lorena,Vega Pablo,Salve María,Díaz-Ondina Marta,Strachan Judith A,Mowat Craig,McDonald Paula J,Carey Francis A,Godber Ian M,Younes Hakim Ben,Rodriguez-Moranta Francisco,Quintero Enrique,Álvarez-Sánchez Victoria,Fernández-Bañares Fernando,Boadas Jaume,Campo Rafel,Bujanda Luis,Garayoa Ana,Ferrandez Ángel,Piñol Virginia,Rodríguez-Alcalde Daniel,Guardiola Jordi,Steele Robert J C,Fraser Callum G, International journal of cancer Prediction models for colorectal cancer (CRC) detection in symptomatic patients, based on easily obtainable variables such as fecal haemoglobin concentration (f-Hb), age and sex, may simplify CRC diagnosis. We developed, and then externally validated, a multivariable prediction model, the FAST Score, with data from five diagnostic test accuracy studies that evaluated quantitative fecal immunochemical tests in symptomatic patients referred for colonoscopy. The diagnostic accuracy of the Score in derivation and validation cohorts was compared statistically with the area under the curve (AUC) and the Chi-square test. 1,572 and 3,976 patients were examined in these cohorts, respectively. For CRC, the odds ratio (OR) of the variables included in the Score were: age (years): 1.03 (95% confidence intervals (CI): 1.02-1.05), male sex: 1.6 (95% CI: 1.1-2.3) and f-Hb (0-<20 µg Hb/g feces): 2.0 (95% CI: 0.7-5.5), (20-<200 µg Hb/g): 16.8 (95% CI: 6.6-42.0), ≥200 µg Hb/g: 65.7 (95% CI: 26.3-164.1). The AUC for CRC detection was 0.88 (95% CI: 0.85-0.90) in the derivation and 0.91 (95% CI: 0.90-093; p = 0.005) in the validation cohort. At the two Score thresholds with 90% (4.50) and 99% (2.12) sensitivity for CRC, the Score had equivalent sensitivity, although the specificity was higher in the validation cohort (p < 0.001). Accordingly, the validation cohort was divided into three groups: high (21.4% of the cohort, positive predictive value-PPV: 21.7%), intermediate (59.8%, PPV: 0.9%) and low (18.8%, PPV: 0.0%) risk for CRC. The FAST Score is an easy to calculate prediction tool, highly accurate for CRC detection in symptomatic patients. 10.1002/ijc.30639
    A Matrix-based Model Predicts Primary Response to Infliximab in Crohn's Disease. Billiet Thomas,Papamichael Konstantinos,de Bruyn Magali,Verstockt Bram,Cleynen Isabelle,Princen Fred,Singh Sharat,Ferrante Marc,Van Assche Gert,Vermeire Severine Journal of Crohn's & colitis BACKGROUND:Prediction of primary non-response [PNR] to anti-tumour necrosis factors [TNFs] in inflammatory bowel disease [IBD] is direly needed to select the optimal therapeutic class for a given patient. We developed a matrix-based prediction tool to predict response to infliximab [IFX] in Crohn's disease [CD] patients. METHODS:This retrospective single-centre study included 201 anti-TNF naïve CD patients who started with IFX induction therapy. PNR occurred in 16 [8%] patients. Clinical, biological [including serum TNF and the IBD serology 6 panel and genetic [the 163 validated IBD risk loci] markers were collected before start. Based on the best fitted regression model, probabilities of primary response to IFX were calculated and arranged in a prediction matrix tool. RESULTS:Multiple logistic regression withheld three final independent predictors [p < 0.05] for PNR: age at first IFX, {odds ratio (OR) (95% confidence interval [CI] of 1.1 (1.0-1.1)}, body mass index [BMI] (0.86 [0.7-1.0]), and previous surgery (4.4 [1.2-16.5]). The accuracy of this prediction model did not improve when the genetic markers were added (area under the curve [AUC] from 0.80 [0.67-0.93] to 0.78 [0.65-0.91]). The predicted probabilities for PNR to IFX increased from 1% to 53% depending on the combination of final predictors. CONCLUSIONS:Readily available clinical factors [age at first IFX, BMI, and previous surgery] outperform serological and IBD risk loci in prediction of primary response to infliximab in this real-life cohort of CD patients. This matrix tool could be useful for guiding physicians and may avoid unnecessary or inappropriate exposure to IFX in IBD patients unlikely to benefit. 10.1093/ecco-jcc/jjv156
    Development of a susceptibility gene based novel predictive model for the diagnosis of ulcerative colitis using random forest and artificial neural network. Li Hanyang,Lai Lijie,Shen Jun Aging Ulcerative colitis is a type of inflammatory bowel disease characterized by chronic and recurrent nonspecific inflammation of the intestinal tract. To find susceptibility genes and develop a novel predictive model of ulcerative colitis, two sets of cases and a control group containing the ulcerative colitis gene expression profile (training set GSE109142 and validation set GSE92415) were downloaded and used to identify differentially expressed genes. A total of 781 upregulated and 127 downregulated differentially expressed genes were identified in GSE109142. The random forest algorithm was introduced to determine 1 downregulated and 29 upregulated differentially expressed genes contributing highest to ulcerative colitis occurrence. Expression data of these 30 genes were transformed into gene expression scores, and an artificial neural network model was developed to calculate differentially expressed genes weights to ulcerative colitis. We established a universal molecular prognostic score (mPS) based on the expression data of the 30 genes and verified the mPS system with GSE92415. Prediction results agreed with that of an independent data set (ROC-AUC=0.9506/PR-AUC=0.9747). Our research creates a reliable predictive model for the diagnosis of ulcerative colitis, and provides an alternative marker panel for further research in disease early screening. 10.18632/aging.103861
    Post-Operative Infection Prediction and Risk Factor Analysis in Colorectal Surgery Using Data Mining Techniques: A Pilot Study. Azimi Kamran,Honaker Michael D,Chalil Madathil Sreenath,Khasawneh Mohammad T Surgical infections Post-operative infections have many negative consequences for patients' health and the healthcare system. Among other things, they increase the recovery time and the risk of re-admission. Also, infection results in penalties for hospitals and decreases the quality performance measures. Surgeons can take preventive actions if they can identify high-risk patients. The purpose of this study was to develop a model to help predict those patients at risk for post-operative infection. A retrospective analysis was conducted on patients with colorectal post-operative infections. Univariable analysis was used to identify the features associated with post-operative infection. Then, a support vector classification-based method was employed to select the right features and build prediction models. Decision tree, support vector machine (SVM), logistic regression, naïve Bayes, neural network, and random forest algorithms were implemented and compared to determine the performance algorithm that best predicted high-risk patients. From 2016 to the first quarter of 2017, 208 patients who underwent colorectal resection were analyzed. The factors with a statistically significant association (p < 0.05) with post-operative infections were elective surgery, origin status, steroid or immunosuppressant use, >10% loss of body weight in the prior six months, serum creatinine concentration, length of stay, unplanned return to the operating room, administration of steroids or immunosuppressants for inflammatory bowel disease, use of a mechanical bowel preparation, various Current Procedural Terminology (CPT) codes, and discharge destination. However, accurate prediction models can be developed with seven factors: age, serum sodium concentration, blood urea nitrogen, hematocrit, platelet count, surgical procedure time, and length of stay. Logistic regression and SVM were stable models for predicting infections. The models developed using the pre-operative features along with the full list of features helped us interpret the results and determine the significant factors contributing to infections. These factors present opportunities for proper interventions to mitigate infection risks and their consequences. 10.1089/sur.2019.138
    Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study. Kugathasan Subra,Denson Lee A,Walters Thomas D,Kim Mi-Ok,Marigorta Urko M,Schirmer Melanie,Mondal Kajari,Liu Chunyan,Griffiths Anne,Noe Joshua D,Crandall Wallace V,Snapper Scott,Rabizadeh Shervin,Rosh Joel R,Shapiro Jason M,Guthery Stephen,Mack David R,Kellermayer Richard,Kappelman Michael D,Steiner Steven,Moulton Dedrick E,Keljo David,Cohen Stanley,Oliva-Hemker Maria,Heyman Melvin B,Otley Anthony R,Baker Susan S,Evans Jonathan S,Kirschner Barbara S,Patel Ashish S,Ziring David,Trapnell Bruce C,Sylvester Francisco A,Stephens Michael C,Baldassano Robert N,Markowitz James F,Cho Judy,Xavier Ramnik J,Huttenhower Curtis,Aronow Bruce J,Gibson Greg,Hyams Jeffrey S,Dubinsky Marla C Lancet (London, England) BACKGROUND:Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. METHODS:We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. FINDINGS:Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%. INTERPRETATION:Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy. FUNDING:Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center. 10.1016/S0140-6736(17)30317-3
    Prediction of Relapse After Anti-Tumor Necrosis Factor Cessation in Crohn's Disease: Individual Participant Data Meta-analysis of 1317 Patients From 14 Studies. Pauwels Renske W M,van der Woude C Janneke,Nieboer Daan,Steyerberg Ewout W,Casanova María J,Gisbert Javier P,Kennedy Nick A,Lees Charlie W,Louis Edouard,Molnár Tamás,Szántó Kata,Leo Eduardo,Bots Steven,Downey Robert,Lukas Milan,Lin Wei C,Amiot Aurelien,Lu Cathy,Roblin Xavier,Farkas Klaudia,Seidelin Jakob B,Duijvestein Marjolijn,D'Haens Geert R,de Vries Annemarie C, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:Tools for stratification of relapse risk of Crohn's disease (CD) after anti-tumor necrosis factor (TNF) therapy cessation are needed. We aimed to validate a previously developed prediction model from the diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressants (STORI) trial, and to develop an updated model. METHODS:Cohort studies were selected that reported on anti-TNF cessation in 30 or more CD patients in remission. Individual participant data were requested for luminal CD patients and anti-TNF treatment duration of 6 months or longer. The discriminative ability (concordance-statistic [C-statistic]) and calibration (agreement between observed and predicted risks) were explored for the STORI model. Next, an updated prognostic model was constructed, with performance assessment by cross-validation. RESULTS:This individual participant data meta-analysis included 1317 patients from 14 studies in 11 countries. Relapses after anti-TNF cessation occurred in 632 of 1317 patients after a median of 13 months. The pooled 1-year relapse rate was 38%. The STORI prediction model showed poor discriminative ability (C-statistic, 0.51). The updated model reached a moderate discriminative ability (C-statistic, 0.59), and included clinical symptoms at cessation (hazard ratio [HR], 2.2; 95% CI, 1.2-4), younger age at diagnosis (HR, 1.5 for A1 (age at diagnosis ≤16 years) vs A2 (age at diagnosis 17 - 40 years); 95% CI, 1.11-1.89), no concomitant immunosuppressants (HR, 1.4; 95% CI, 1.18-172), smoking (HR, 1.4; 95% CI, 1.15-1.67), second line anti-TNF (HR, 1.3; 95% CI, 1.01-1.69), upper gastrointestinal tract involvement (HR, 1.3 for L4 vs non-L4; 95% CI, 0.96-1.79), adalimumab (HR, 1.22 vs infliximab; 95% CI, 0.99-1.50), age at cessation (HR, 1.2 per 10 years younger; 95% CI, 1-1.33), C-reactive protein (HR, 1.04 per doubling; 95% CI, 1.00-1.08), and longer disease duration (HR, 1.07 per 5 years; 95% CI, 0.98-1.17). In subanalysis, the discriminative ability of the model improved by adding fecal calprotectin (C-statistic, 0.63). CONCLUSIONS:This updated prediction model showed a reasonable discriminative ability, exceeding the performance of a previously published model. It might be useful to guide clinical decisions on anti-TNF therapy cessation in CD patients after further validation. 10.1016/j.cgh.2021.03.037
    Combined Endoscopic/Sonographic-based Risk Matrix Model for Predicting One-year Risk of Surgery: A Prospective Observational Study of a Tertiary Centre Severe/Refractory Crohn's Disease Cohort. Rispo Antonio,Imperatore Nicola,Testa Anna,Bucci Luigi,Luglio Gaetano,De Palma Giovanni Domenico,Rea Matilde,Nardone Olga Maria,Caporaso Nicola,Castiglione Fabiana Journal of Crohn's & colitis Background:In the management of Crohn's disease [CD] patients, having a simple score combining clinical, endoscopic, and imaging features to predict the risk of surgery could help to tailor treatment more effectively. Aims:We aimed to prospectively evaluate the 1-year risk factors for surgery in refractory/severe CD and to generate a risk matrix for predicting the probability of surgery at 1 year. Methods:CD patients needing a disease re-assessment at our tertiary inflammatory bowel disease [IBD] centre underwent clinical, laboratory, endoscopic, and bowel sonography [BS] examinations within 1 week. The optimal cut-off values in predicting surgery were identified using receiver operating characteristic [ROC] curves for the Simple Endoscopic Score for CD [SES-CD], bowel wall thickness [BWT] at BS, and small bowel CD extension at BS. Binary logistic regression and Cox regression were then carried out. Finally, the probabilities of surgery were calculated for selected baseline levels of covariates and results were arranged in a prediction matrix. Results:Of 100 CD patients, 30 underwent surgery within 1 year. SES-CD ≥9 (odds ratio [OR] 15.3; p <0.001], BWT ≥7 mm [OR 15.8; p <0.001], small bowel CD extension at BS ≥33 cm [OR 8.23; p <0.001], and stricturing/penetrating behaviour [OR 4.3; p <0.001] were the only independent factors predictive of surgery at 1 year, based on binary logistic and Cox regressions. Our matrix model combined these risk factors, and the probability of surgery ranged from 0.48% to 87.5% [16 combinations]. Conclusions:Our risk matrix combining clinical, endoscopic, and ultrasonographic findings can accurately predict the 1-year risk of surgery in patients with severe/refractory CD requiring a disease re-evaluation. This tool could be of value in clinical practice, serving as the basis for a tailored management of CD patients. 10.1093/ecco-jcc/jjy032
    Development and Validation of a Novel Prediction Model for Differential Diagnosis Between Crohn's Disease and Intestinal Tuberculosis. Bae Jung Ho,Park Sang Hyoung,Ye Byong Duk,Kim Seon-Ok,Cho Yun Kyung,Youn Eun Ja,Lee Ho-Su,Hwang Sung Wook,Yang Dong-Hoon,Kim Kyung-Jo,Byeon Jeong-Sik,Myung Seung-Jae,Yang Suk-Kyun Inflammatory bowel diseases BACKGROUND:Although colonoscopy is useful for differentiating between Crohn's disease (CD) and intestinal tuberculosis (ITB), the technique has limitations. We developed a practical prediction model for differentiating between CD and ITB using laboratory and radiologic parameters and colonoscopic characteristics. METHODS:We prospectively enrolled 80 patients newly diagnosed with CD (n = 40) and ITB (n = 40). We developed a new prediction score by integrating colonoscopic, laboratory, and radiologic parameters. The score's predictive ability was validated on an additional 37 patients. RESULTS:The accuracy of colonoscopic scoring for differentiation was 81.2% (65/80), with 65.0% sensitivity for CD and 97.5% for ITB. In multivariate analysis, positive IgA and/or IgG anti-Saccharomyces cerevisiae antibody and involvement of the proximal intestine were the independent laboratory and radiologic parameters for CD, and positive QuantiFERON-TB Gold In-Tube Test and typical pulmonary TB findings were the parameters for ITB. A new prediction scoring combining colonoscopic, laboratory, and radiologic factors increased the accuracy of diagnosis from 81.2% to 96.3% (77/80). The CD prediction score (from -2 to 2) estimated the likelihood of CD, from 0.3% for patients scoring -2 to 100% for patients scoring 2. The area under the receiver operating characteristic curve of the score was 0.990 in the development group and 0.981 in the validation group. CONCLUSIONS:The new prediction model using a CD prediction score can be useful for calculating the probability of either CD or ITB at initial evaluation (NCT01392365). 10.1097/MIB.0000000000001162
    Biomarker-Based Models Outperform Patient-Reported Scores in Predicting Endoscopic Inflammatory Disease Activity. Morris Marc W,Stewart Samuel A,Heisler Courtney,Sandborn William J,Loftus Edward V,Zello Gordon A,Fowler Sharyle A,Jones Jennifer L Inflammatory bowel diseases Background:The Crohn's Disease Activity Index (CDAI), a scoring index including patient-reported outcomes (PROs), has known limitations for measuring intestinal inflammatory disease burden. Noninvasive markers of inflammation could prove more accurate than PROs; thus, regulatory authorities are exploring the use of PROs and endoscopic data as coprimary end points in clinical trials. The aim of this study was to assess the predictive ability of individual components of the CDAI, along with biomarker concentrations, to create models for predicting endoscopic disease activity. Methods:Between 2004 and 2006, 164 patients with established Crohn's disease (CD) undergoing clinically indicated ileocolonoscopy were recruited. Individual CDAI variables and fecal calprotectin (FC) were selected to explore their predictive accuracy for endoscopic disease activity, with the Simple Endoscopic Score-Crohn's Disease (SES-CD) as the outcome variable. Simple Poisson regression was performed on each variable, and 2 multivariate models were created (PRO-exclusive and PRO+FC [PRO+]). Additional analyses explored the patient-level agreement between models. Results:Number of liquid stools, abdominal pain, hematocrit (Hct), FC, and high-sensitivity C-reactive protein (hsCRP) correlated significantly with the SES-CD. For the prediction of SES-CD (>7 vs ≤6), the area under the curve (AUC) was 0.81, with 63% and 88% sensitivity and specificity, for the PRO+ model, compared with a 0.56 AUC, with 61% and 55%, respectively, for the PRO model. Intra-individual comparison revealed the PRO+ model to be superior in the prediction of endoscopically active disease. Conclusions:The inclusion of biomarkers significantly improved predictive accuracy for endoscopic disease activity compared with PRO-exclusive models. 10.1093/ibd/izx018
    Development and Validation of a Scoring System to Predict Outcomes of Vedolizumab Treatment in Patients With Crohn's Disease. Dulai Parambir S,Boland Brigid S,Singh Siddharth,Chaudrey Khadija,Koliani-Pace Jenna L,Kochhar Gursimran,Parikh Malav P,Shmidt Eugenia,Hartke Justin,Chilukuri Prianka,Meserve Joseph,Whitehead Diana,Hirten Robert,Winters Adam C,Katta Leah G,Peerani Farhad,Narula Neeraj,Sultan Keith,Swaminath Arun,Bohm Matthew,Lukin Dana,Hudesman David,Chang John T,Rivera-Nieves Jesus,Jairath Vipul,Zou G Y,Feagan Brian G,Shen Bo,Siegel Corey A,Loftus Edward V,Kane Sunanda,Sands Bruce E,Colombel Jean-Frederic,Sandborn William J,Lasch Karen,Cao Charlie Gastroenterology BACKGROUND & AIMS:As more treatment options for inflammatory bowel diseases become available, it is important to identify patients most likely to respond to different therapies. We created and validated a scoring system to identify patients with Crohn's disease (CD) who respond to vedolizumab. METHODS:We collected data from the GEMINI 2 phase 3 trial of patients with active CD treated with vedolizumab for 26 weeks (n = 814) and performed logistic regression analysis to identify factors associated with clinical, steroid-free, and durable remission (derivation set). We used these data to develop a clinical decision support tool, which we validated using data from 366 participants in a separate clinical practice observational cohort of patients with active CD treated with vedolizumab for 26 weeks (the VICTORY cohort). We evaluated the ability of this tool to identify patients in clinical remission or corticosteroid-free remission, or those with mucosal healing (MH), clinical remission with MH, or corticosteroid-free remission with MH after vedolizumab therapy using receiver operating characteristic area under the curve (AUC) analyses. The primary outcome was to develop and validate a list of factors associated with achieving remission by vedolizumab in patients with active CD. RESULTS:In the derivation analysis, we identified absence of previous treatment with a tumor necrosis factor antagonist (+3 points), absence of prior bowel surgery (+2 points), absence of prior fistulizing disease (+2 points), baseline level of albumin (+0.4 points per g/L), and baseline concentration of C-reactive protein (reduction of 0.5 points for values between 3.0 and 10.0 mg/L and 3.0 points for values >10.0 mg/L) as factors associated with remission. In the validation set, our model identified patients in clinical remission with an AUC of 0.67, patients in corticosteroid-free remission with an AUC of 0.66, patients with MH with an AUC of 0.72, patients in clinical remission with MH with an AUC of 0.73, and patients in corticosteroid-free clinical remission with MH with an AUC of 0.75. A cutoff value of 13 points identified patients in clinical remission after vedolizumab therapy with 92% sensitivity, patients in corticosteroid-free remission with 94% sensitivity, patients with MH with 98% sensitivity, patients with clinical remission and MH with 100% sensitivity, and patients with corticosteroid-free clinical remission with MH with 100% sensitivity. CONCLUSIONS:We developed and validated a scoring system to identify patients with CD most likely to respond to 26 weeks of vedolizumab therapy. Further studies are needed to optimize its accuracy in select populations and determine its cost-effectiveness. 10.1053/j.gastro.2018.05.039
    Creeping Fat Assessed by Small Bowel MRI Is Linked to Bowel Damage and Abdominal Surgery in Crohn's Disease. Althoff Patrick,Schmiegel Wolff,Lang Gernot,Nicolas Volkmar,Brechmann Thorsten Digestive diseases and sciences BACKGROUND:Crohn's disease (CD) leads to bowel damage and surgery in a significant proportion of patients. AIMS:The aim of the study was to evaluate the predictive value of creeping fat assessed by small bowel MRI in CD patients. METHODS:CD patients undergoing small bowel MRI were included in a retrospective observational cohort study. Clinical findings were extracted and correlated with radiological outcome measures. Logistic regression analysis was performed to assess predictors associated with a complicated course and surgery within 2 years and long-term follow-up. RESULTS:Ninety patients (49% female, median follow-up 93 months) were included. Creeping fat was identified in 21.1%. Of these patients, 68% and 79% developed bowel damage (p < .05) and 42% and 63% of patients revealing creeping fat underwent surgery within 2 years following MRI and total follow-up, respectively. The presence of creeping fat [odds ratio (OR) 4.0], inflammatory stenosis (OR 3.7), multisegmental (small) bowel (OR 4.5 and 3.8), and proximal small bowel inflammation (OR 5.0) were associated with inferior outcome (p < .05) in a univariate analysis. Creeping fat was independently associated with a disabling course, bowel damage, and surgery (OR 3.5 each, p < .05) in a multivariate analysis model. CONCLUSION:Creeping fat identified by small bowel MRI is associated with a complicated course and abdominal surgery in CD. Our data adds evidence that small bowel MRI facilitates risk stratification in order to define a patient at risk of disease-related complications in CD. [DRKS00011727, www.germanctr.de/ ]. 10.1007/s10620-018-5303-1
    Predicting inadequate bowel preparation for colonoscopy in participants receiving split-dose bowel preparation: development and validation of a prediction score. Dik Vincent K,Moons Leon M G,Hüyük Melek,van der Schaar Peter,de Vos Tot Nederveen Cappel Wouter H,Ter Borg Pieter C J,Meijssen Maarten A C,Ouwendijk Rob J T H,Le Fèvre Doris M,Stouten Merijn,van der Galiën Onno,Hiemstra Theo J,Monkelbaan Jan F,van Oijen Martijn G H,Siersema Peter D, Gastrointestinal endoscopy BACKGROUND:Adequate bowel preparation is important for optimal colonoscopy. It is important to identify patients at risk for inadequate bowel preparation because this allows taking precautions in this specific group. OBJECTIVE:To develop a prediction score to identify patients at risk for inadequate bowel preparation who may benefit from an intensified bowel cleansing regimen. DESIGN:Patient and colonoscopy data were prospectively collected, whereas clinical data were retrospectively collected for a total of 1996 colonoscopies in participants who received split-dose bowel preparation. Multivariate logistic regression analyses were conducted in a random two-thirds of the cohort to develop a prediction model. Validation and evaluation of the discriminative power of the prediction model were performed within the remaining one-third of the cohort. SETTING:Four centers, including one academic and three medium-to-large size nonacademic centers. PATIENTS:Consecutive colonoscopies in November and December 2012. Mean age was 57.3 ± 15.9 years, 45.8% were male and indications for colonoscopy were screening and/or surveillance (27%), abdominal symptoms and/or blood loss and/or anemia (60%), inflammatory bowel disease (9%), and others (4%). INTERVENTIONS:Colonoscopy. MAIN OUTCOME MEASUREMENTS:Inadequate bowel preparation defined as Boston Bowel Preparation Scale score <6. RESULTS:A total of 1331 colonoscopies were included in the development cohort, of which 172 (12.9%) had an inadequate bowel preparation. Independent factors included in the prediction model were American Society of Anesthesiologists Physical Status Classification System score ≥3, use of tricyclic antidepressants, use of opioids, diabetes, chronic constipation, history of abdominal and/or pelvic surgery, history of inadequate bowel preparation, and current hospitalization. The discriminative ability of the scale was good, with an area under the curve of 0.77 in the validation cohort. LIMITATIONS:Study design partially retrospective, no data on patient compliance. CONCLUSION:We developed a validated, easy-to-use prediction scale that can be used to identify subjects with an increased risk of inadequate bowel preparation with good accuracy. 10.1016/j.gie.2014.09.066
    A User-Friendly Prediction Tool to Identify Colectomy Risk in Patients With Ulcerative Colitis. Dalal Rahul S,Osterman Mark T,Buchner Anna M,Praestgaard Amy,Lewis James D,Lichtenstein Gary R Inflammatory bowel diseases BACKGROUND:Many patients with ulcerative colitis (UC) fear the potential side effects of immunosuppressive therapies. However, those with medically refractory disease often require total proctocolectomy (TPC) with a permanent ostomy or pouch, which may reduce quality of life. Prior studies have identified TPC predictors; however, no clinically useful prognostic tools exist to guide shared therapeutic decision-making. We therefore sought to develop a prediction tool of future TPC risk in UC patients. METHODS:In this retrospective study, clinic charts of UC patients were reviewed from January 1, 2017, to December 31, 2017. Cases had TPC performed for refractory UC after January 1, 2008. Controls had no prior UC surgery. Clinical data were assessed 1-12 months preceding TPC or clinic visit for cases and controls, respectively. We randomly selected two-thirds of patients to develop a TPC prediction model using multivariable logistic regression. One-third was reserved for model validation. RESULTS:We identified 115 cases and 325 controls. TPC predictors included albumin, 9-point Mayo score >5, Mayo endoscopic subscore >1, and corticosteroid use within 6 months. The areas under the receiver operating characteristic curve for the multivariable model were 0.94 (95% confidence interval [CI], 0.92-0.95) and 0.92 (95% CI, 0.89-0.95) for the test and validation cohorts, respectively. The validation cohort demonstrated a significant difference in calculated probability distributions between patients who did and did not have TPC (P < 0.01). We incorporated our model into a web-based application to allow convenient calculation of a patient's TPC risk. CONCLUSIONS:We created a user-friendly tool to assess TPC risk in UC. Prospective assessment will determine its utility for shared therapeutic decision-making. 10.1093/ibd/izz014
    Extended Venous Thromboembolism Prophylaxis After Elective Surgery for IBD Patients: Nomogram-Based Risk Assessment and Prediction from Nationwide Cohort. Benlice Cigdem,Holubar Stefan D,Gorgun Emre,Stocchi Luca,Lipman Jeremy M,Kalady Matthew F,Champagne Bradley J,Steele Scott R Diseases of the colon and rectum BACKGROUND:Identification of risk factors for postoperative venous thromboembolism is an important step to reduce the morbidity associated with this potentially preventable complication after elective surgery for patients with IBD. OBJECTIVE:This study aimed to determine the risk factors for 30-day venous thromboembolism after abdominal surgery for patients with venous thromboembolism, identify potential indications for extended thromboprophylaxis, and develop a nomogram for prediction of risk. DESIGN:This is a retrospective cohort study from a prospectively collected database. SETTING:The American College of Surgeons National Surgical Quality Improvement Program Participant User File from 2005 to 2016 was used for data analysis. PATIENTS:All patients with IBD undergoing elective abdominopelvic bowel surgery were included. MAIN OUTCOME MEASURES:The primary outcomes were the incidence of in-hospital and postdischarge venous thromboembolism within 30 days of the index abdominopelvic surgery. RESULTS:A total of 24,182 patients met the inclusion criteria. Thirty-day total and postdischarge rates of venous thromboembolism were 2.5% (n = 614) and 1% (n =252). Forty-one percent (252/614) of venous thromboembolism events occurred after hospital discharge. Univariate analysis assessed 37 variables for association with study outcomes. On multivariate logistic regression analysis, older age, steroid use, bleeding disorders, open surgery, hypertension, longer operative time, and preoperative hospitalization were associated with venous thromboembolism before discharge and also postoperative transfusion, steroid use, pelvic and enterocutaneous fistula surgery, and longer operative time were associated with venous thromboembolism after discharge. A nomogram was constructed for each outcome, translating multivariate model parameter estimates into a visual scoring system where the estimated probability of venous thromboembolism can be calculated. LIMITATIONS:This study was limited by its retrospective nature and the limitations inherent to a database. CONCLUSION:Given the higher risk of venous thromboembolism in patients with IBD after elective abdominopelvic surgery compared with other indications, an accurate prediction of venous thromboembolism before and after discharge using the proposed nomogram can facilitate decision making for individualized extended thromboprophylaxis in the preoperative setting as a screening tool. See Video Abstract at http://links.lww.com/DCR/A711. 10.1097/DCR.0000000000001189
    Cigarette Smoke Increases Risk for Colorectal Neoplasia in Inflammatory Bowel Disease. van der Sloot Kimberley W J,Tiems Johan L,Visschedijk Marijn C,Festen Eleonora A M,van Dullemen Hendrik M,Weersma Rinse K,Kats-Ugurlu Gursah,Dijkstra Gerard Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:Patients with inflammatory bowel disease are at increased risk of colorectal neoplasia (CRN) due to mucosal inflammation. As current surveillance guidelines form a burden on patients and healthcare costs, stratification of high-risk patients is crucial. Cigarette smoke reduces inflammation in ulcerative colitis (UC) but not Crohn's disease (CD) and forms a known risk factor for CRN in the general population. Due to this divergent association, the effect of smoking on CRN in IBD is unclear and subject of this study. METHODS:In this retrospective cohort study, 1,386 IBD patients with previous biopsies analyzed and reported in the PALGA register were screened for development of CRN. Clinical factors and cigarette smoke were evaluated. Patients were stratified for guideline-based risk of CRN. Cox-regression modeling was used to estimate the effect of cigarette smoke and its additive effect within the current risk stratification for prediction of CRN. RESULTS:153 (11.5%) patients developed CRN. Previously described risk factors, i.e. first-degree family member with CRN in CD (p-value=.001), presence of post-inflammatory polyps in UC (p-value=.005), were replicated. Former smoking increased risk of CRN in UC (HR 1.73; 1.05-2.85), whereas passive smoke exposure yielded no effect. For CD, active smoking (2.20; 1.02-4.76) and passive smoke exposure (1.87; 1.09-3.20) significantly increased CRN risk. Addition of smoke exposure to the current risk-stratification model significantly improved model fit for CD. CONCLUSIONS:This study is the first to describe the important role of cigarette smoke in CRN development in IBD patients. Adding this risk factor improves the current risk stratification for CRN surveillance strategies. 10.1016/j.cgh.2021.01.015
    Noninvasive Fecal Immunochemical Testing and Fecal Calprotectin Predict Mucosal Healing in Inflammatory Bowel Disease: A Prospective Cohort Study. Ma Christopher,Lumb Rowan,Walker Emily V,Foshaug Rae R,Dang ThucNhi T,Verma Sanam,Huang Vivian W,Kroeker Karen I,Wong Karen,Dieleman Levinus A,Fedorak Richard N,Halloran Brendan P Inflammatory bowel diseases BACKGROUND:The noninvasive biomarkers fecal immunochemical testing (FIT) and fecal calprotectin (FCP) are sensitive for prediction of mucosal inflammation in inflammatory bowel disease. However, neither test has yet been shown to independently and accurately predict mucosal healing (MH). We aimed to assess the specificity of noninvasive FIT and FCP for MH prediction. METHODS:In this prospective cohort study of adult inflammatory bowel disease outpatients presenting for colonoscopy, stool samples for FIT and FCP were collected 48 hours before endoscopy. Using MH defined by Simple Endoscopic Score for Crohn's disease (SES-CD = 0), Rutgeert's score (i0), and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS = 3), receiver operator characteristic curves were plotted, and sensitivity, specificity, positive and negative predictive values, and areas under the curve were calculated. Multivariate logistic regression analysis was used to develop a clinical model for noninvasively predicting MH. RESULTS:Eighty patients (40 Crohn's disease and 40 ulcerative colitis) were enrolled. The specificities of FIT <100 ng/mL and FCP <250 μg/g for MH were 0.57 (95% confidence interval, 0.38-0.74) and 0.77 (0.57-0.89), respectively. Positive predictive values for MH for FIT <100 ng/mL and FCP <250 μg/g were 0.78 (0.64-0.87) and 0.77 (0.58-0.90), respectively. In multivariate modeling, combining FIT, FCP, and clinical symptomatic remission improved specificity for MH to 0.90 (0.72-0.97) with positive predictive values of 0.84 (0.60-0.96). Areas under the curve for FIT was higher for patients with ulcerative colitis (0.88) than for patients with Crohn's disease (0.69, P = 0.05). CONCLUSIONS:FIT and FCP have similar performance characteristics for identifying MH. Combined, low FIT, low FCP, and clinical remission are specific for MH. 10.1097/MIB.0000000000001173
    A simple risk score for predicting surgical site infections in inflammatory bowel disease. Alavi Karim,Sturrock Paul R,Sweeney W B,Maykel Justin A,Cervera-Servin J A,Tseng Jennifer,Cook E F Diseases of the colon and rectum PURPOSE:Patients with inflammatory bowel disease are often at highest risk for surgical site infections. We sought to define the predictors of surgical site infections and to develop a risk score for predicting those at highest risk. METHODS:Patients undergoing a bowel resection for Crohn's disease or ulcerative colitis were identified from National Surgical Quality Improvement Program 2008. Univariate and multivariate analyses were conducted to identify predictors of surgical site infections. Clinically relevant prediction categories were developed and the predictive behavior of the model was validated by use of National Surgical Quality Improvement Program 2007. An integer-based scoring system risk score was created proportional to the logistic regression coefficients, grouping patients into categories of similar risk. RESULTS:We identified 271,368 patients; 3981 of these patients underwent an operation for Crohn's disease (n = 2895) or ulcerative colitis (n = 1086). Nine hundred (22.6%) patients developed surgical site infections. Predictors included weight loss, smoking, emergent surgery, wound class, operative time (minutes), and an ASA score >2. A risk score was developed by stratifying patients into low (0-5), 15.6%; medium (6-8), 25.2%; and high (>8), 36.1% risk. CONCLUSIONS:Patients with inflammatory bowel disease are at high risk for surgical site infections. Preoperative factors including weight loss, smoking, emergent surgery and an ASA score >2 are strong predictors of surgical site infections. Operative time and wound class are important intraoperative predictors. A risk score, based on pre- and intraoperative variables, can be used to identify patients at highest risk of developing surgical site infections. This may allow for appropriate process measures to be implemented to prevent and lessen the impact of surgical site infections in this high-risk population. 10.1007/DCR.0b013e3181f1f0fd
    Do clinical and laboratory parameters predict thiopurine metabolism and clinical outcome in patients with inflammatory bowel diseases? Frick Sven,Müller Daniel,Kullak-Ublick Gerd A,Jetter Alexander European journal of clinical pharmacology PURPOSE:The thiopurines azathioprine and 6-mercaptopurine are frequently used for remission maintenance in patients with inflammatory bowel diseases. However, there are therapy failures, and it is unclear whether clinical and laboratory parameters can be used to predict thiopurine metabolite concentrations (as a surrogate for adequate remission maintenance therapy) and clinical outcome in these patients. METHODS:In this retrospective analysis of clinical routine patient data, multivariate statistical models based on Linear Mixed Models regression and Generalized Estimating Equations logistic regression were developed. The adequacy of the models was assessed using Pearson's correlation and a receiver operating characteristic curve. RESULTS:This study included 273 patients and 1158 thiopurine metabolite measurements as well as routine laboratory and clinical data. In the statistical models, thiopurine metabolite concentrations and the odds of non-remission based on different clinical and laboratory parameters were computed. Correlation (r) between predicted and measured thiopurine metabolites were 0.40 (p < 0.001) for 6-thioguanine nucleotides and 0.53 (p < 0.001) for 6-methyl-mercaptopurine nucleotides, respectively. The model for remission classified data sets in remission and non-remission with a sensitivity of 63% and a specificity of 73%. The area under the receiver operating characteristic curve of the model was 0.72. CONCLUSIONS:Although the models are not yet accurate enough to be used in clinical routine, model-based prediction of thiopurine metabolite concentrations and of outcome is feasible. Until more accurate models are developed and validated, traditional therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel diseases under thiopurine therapy stays the best tool to individualize therapy. 10.1007/s00228-018-02616-7
    Prevalence and risk factors of nonalcoholic fatty liver disease in patients with inflammatory bowel diseases: A cross-sectional and longitudinal analysis. Hoffmann Peter,Jung Victoria,Behnisch Rouven,Gauss Annika World journal of gastroenterology BACKGROUND:Nonalcoholic fatty liver disease (NAFLD) is common in the German population, with an even higher prevalence in inflammatory bowel disease patients. AIM:To investigate the risk factors for NAFLD in inflammatory bowel disease patients. METHODS:This monocentric retrospective study with a cross-sectional and a longitudinal part included 694 patients. Inclusion criteria were diagnosed inflammatory bowel disease, age ≥ 18 years, availability of at least one abdominal ultrasound. Patients with infectious or suspected alcoholic fatty liver disease were excluded. NAFLD was defined by increased echogenicity at liver ultrasound. Demographic characteristics, disease activity and medications were analyzed as potential risk factors. Parameters influencing the course of NAFLD were identified by a generalized linear mixed model. RESULTS:Forty-eight percent of Crohn's disease (CD) patients and 44% of ulcerative colitis patients suffered from NAFLD. Its occurrence was associated with greater age, hypertension and body mass index (BMI) in both groups, and with higher disease activity and dyslipidemia in CD. 2467 ultrasound results were included in the longitudinal analysis. Risk factors for NAFLD were age, BMI, higher disease activity, bowel resection(s), endoscopic activity and azathioprine use in CD; and BMI and endoscopic activity in ulcerative colitis. CONCLUSION:NAFLD was highly prevalent in this cohort of German inflammatory bowel disease patients. Its risk increased mainly with rising age and BMI. This analysis provides a rationale for non-invasive liver screening in inflammatory bowel disease patients. 10.3748/wjg.v26.i46.7367
    Faecal calprotectin in suspected paediatric inflammatory bowel disease. Degraeuwe Pieter L J,Beld Monique P A,Ashorn Merja,Canani Roberto Berni,Day Andrew S,Diamanti Antonella,Fagerberg Ulrika L,Henderson Paul,Kolho Kaija-Leena,Van de Vijver Els,van Rheenen Patrick F,Wilson David C,Kessels Alfons G H Journal of pediatric gastroenterology and nutrition OBJECTIVES:The diagnostic accuracy of faecal calprotectin (FC) concentration for paediatric inflammatory bowel disease (IBD) is well described at the population level, but not at the individual level. We reassessed the diagnostic accuracy of FC in children with suspected IBD and developed an individual risk prediction rule using individual patient data. METHODS:MEDLINE, EMBASE, DARE, and MEDION databases were searched to identify cohort studies evaluating the diagnostic performance of FC in paediatric patients suspected of having IBD. A standard study-level meta-analysis was performed. In an individual patient data meta-analysis, we reanalysed the diagnostic accuracy on a merged patient dataset. Using logistic regression analysis we investigated whether and how the FC value and patient characteristics influence the diagnostic precision. A prediction rule was derived for use in clinical practice and implemented in a spreadsheet calculator. RESULTS:According to the study-level meta-analysis (9 studies, describing 853 patients), FC has a high overall sensitivity of 0.97 (95% confidence interval [CI] 0.92-0.99) and a specificity of 0.70 (0.59-0.79) for diagnosing IBD. In the patient-level pooled analysis of 742 patients from 8 diagnostic accuracy studies, we calculated that at an FC cutoff level of 50 μg/g there would be 17% (95% CI 15-20) false-positive and 2% (1-3) false-negative results. The final logistic regression model was based on individual data of 545 patients and included both FC level and age. The area under the receiver operating characteristic curve of this derived prediction model was 0.92 (95% CI 0.89-0.94). CONCLUSIONS:In high-prevalence circumstances, FC can be used as a noninvasive biomarker of paediatric IBD with only a small risk of missing cases. To quantify the individual patients' risk, we developed a simple prediction model based on FC concentration and age. Although the derived prediction rule cannot substitute the clinical diagnostic process, it can help in selecting patients for endoscopic evaluation. 10.1097/MPG.0000000000000615
    Collecting New Peak and Intermediate Infliximab Levels to Predict Remission in Inflammatory Bowel Diseases. Liefferinckx Claire,Bottieau Jérémie,Toubeau Jean-François,Thomas Debby,Rahier Jean-François,Louis Edouard,Baert Filip,Dewint Pieter,Pouillon Lieven,Lambrecht Guy,Vallée François,Vermeire Severine,Bossuyt Peter,Franchimont Denis Inflammatory bowel diseases BACKGROUND:The loss of response to infliximab is a challenge for clinicians in the management of inflammatory bowel disease (IBD). Mounting evidence suggests that therapeutic drug monitoring at induction may predict remission during maintenance. The aim of the study was to improve predictive models of remission by exploring new peak and intermediate infliximab measurements during induction. METHODS:This was a prospective multicenter study evaluating the pharmacokinetics of infliximab during induction in a pioneer cohort of 63 patients with IBD. Pharmacokinetics data including peak, intermediate, and trough levels were combined with clinical and biological parameters and were subsequently fed into tailored logistic regression and tree-based techniques to predict remission at week 30. RESULTS:Infliximab peak levels at week 2, intermediate levels at week 3, and trough levels at week 6 were correlated with remission at week 30. Predictive models exhibited an increased accuracy over the successive timepoints of the induction with key inputs such as albumin, C-reactive protein, eosinophils, neutrophils, lymphocytes, intermediate level at week 3, trough level at week 6, and age at diagnosis. Our predictive model of remission at week 30 was obtained with an area under the receiver operating characteristic curve of 0.9 ± 0.12, a sensitivity of 89%, and a specificity of 75%. CONCLUSIONS:This study showed the clinical relevance of measuring new infliximab levels to predict remission in patients with IBD. These findings lay the foundation for a personalized medicine in which biotherapies could be monitored at an early stage, thereby improving patients' clinical management. 10.1093/ibd/izab042
    Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling. Kimura Koji,Yoshida Atsushi,Katagiri Fumihiko,Takayanagi Risa,Yamada Yasuhiko Biopharmaceutics & drug disposition Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases. 10.1002/bdd.2198
    Comparison of a novel predictor of venous thromboembolic complications in inflammatory bowel disease with current predictors. Ohta Yuki,Arai Makoto,Nakagawa Tomoo,Akizue Naoki,Ishikawa Kentaro,Hamanaka Shinsaku,Koseki Hirotaka,Taida Takashi,Okimoto Kenichiro,Saito Keiko,Yoshihama Sayuri,Maruoka Daisuke,Matsumura Tomoaki,Katsuno Tatsuro,Kato Naoya Journal of gastroenterology and hepatology BACKGROUND AND AIM:Venous thromboembolism (VTE) is a common complication of inflammatory bowel disease (IBD). The aim of the present study was to identify predictors of VTE in hospitalized patients with IBD. METHODS:Patients with IBD who were hospitalized from February 2015 to March 2016 at the Chiba University Hospital were included. VTE was detected using enhanced computed tomography, and VTE onset within 2 months after admission was assessed. Predictors of VTE onset were investigated with clinical factors during hospitalization. Availability of the Caprini risk assessment model and Padua prediction score at the time of admission was also assessed. RESULTS:Seventy-two patients with IBD were hospitalized, and central venous catheters were placed in 43 of the 72 patients. During the observation period, VTE occurred in six patients (8.3%); however, none died as a result of the condition. Cox proportional hazards regression analysis identified D-dimer values on admission as a risk factor that was highly associated with VTE onset (hazard ratio = 1.590; 95% confidence interval, 1.132-2.233; P = 0.007) and significantly predicted the occurrence of VTE using the receiver operating characteristic curve (P = 0.005, area under the curve = 0.893). However, Caprini risk assessment model and Padua prediction scores were not useful tools for predicting VTE onset in patients with IBD. CONCLUSION:In hospitalized patients with IBD, D-dimer values were highly associated with VTE onset. Therefore, measurement of D-dimer values on admission is critical for the management of thromboembolic complications in patients with IBD. 10.1111/jgh.14472
    Usefulness of population pharmacokinetics to optimize the dosage regimen of infliximab in inflammatory bowel disease patients. Gil Candel Mayte,Gascón Cánovas Juan José,Gómez Espín Rosa,Nicolás de Prado Isabel,Rentero Redondo Lorena,Urbieta Sanz Elena,Iniesta Navalón Carles Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva INTRODUCTION:infliximab is used in inflammatory bowel disease, which has a great inter-individual pharmacokinetic variability. Thus, it is necessary to individualize the therapy in many cases. The main objective of our study was to compare two methods of a dose adjustment strategy using therapeutic drug monitoring: a) based on an algorithm and b) based on Bayesian prediction, to achieve an optimal infliximab trough level in patients with inflammatory bowel diseases. The secondary objective was to evaluate the predictive performance of a population pharmacokinetic model of infliximab in patients with inflammatory bowel diseases and therefore, its clinical utility. Furthermore, the factors associated with a suboptimal adjustment of the model were analyzed. METHODS:a retrospective observational cohort analysis was performed of patients with inflammatory bowel disease and available serum levels of infliximab. The relationship between trough concentration and dosing strategy was compared in both groups. The external validation of a previously published population pharmacokinetic model was performed using the NONMEM software. The mean prediction error and mean absolute prediction error were calculated to evaluate the predictive performance of the model. RESULTS:a total of 94 infliximab serum samples were obtained from 47 patients. After the adjustment, a total of 30 patients (63.8 %) achieved optimal infliximab trough levels. A dosing strategy based on Bayesian was associated with optimal infliximab trough levels that were higher than the strategy based on an algorithm (OR: 8.94 [95 % CI: 2.24 - 35.6], p = 0.001). For the individual predictions, the mean prediction error was 0.118 µg/ml (95 % CI: -0.149-0.384) and the mean absolute prediction error was 0.935 µg/ml (95 % CI: 0.569-1.075). CONCLUSIONS:the application of a population pharmacokinetic model based on Bayesian prediction is an important advance in the optimization of infliximab dosage in the treatment of inflammatory bowel disease. 10.17235/reed.2020.6857/2020
    Fecal microbiota transplantation results in bacterial strain displacement in patients with inflammatory bowel diseases. Zou Manli,Jie Zhuye,Cui Bota,Wang Honggang,Feng Qiang,Zou Yuanqiang,Zhang Xiuqing,Yang Huanming,Wang Jian,Zhang Faming,Jia Huijue FEBS open bio Fecal microbiota transplantation (FMT), which is thought to have the potential to correct dysbiosis of gut microbiota, has been used to treat inflammatory bowel disease (IBD) for almost a decade. Here, we report an interventional prospective cohort study performed to elucidate the extent of and processes underlying microbiota engraftment in IBD patients after FMT treatment. The cohort included two categories of patients: (a) patients with moderate to severe Crohn's disease (CD) (Harvey-Bradshaw Index ≥ 7, n = 11) and (b) patients with ulcerative colitis (UC) (Montreal classification S2 and S3, n = 4). All patients were treated with a single FMT (via mid-gut, from healthy donors), and follow-up visits were performed at baseline, 3 days, 1 week, and 1 month after FMT (missing time points included). At each follow-up time point, fecal samples and clinical metadata were collected. For comparative analysis, 10 fecal samples from 10 healthy donors were included to represent the diversity level of normal gut microbiota. Additionally, the metagenomic data of 25 fecal samples from five individuals with metabolic syndrome who underwent autologous FMT treatment were downloaded from a previous published paper to represent fluctuations in microbiota induced during FMT. All fecal samples underwent shotgun metagenomic sequencing. We found that 3 days after FMT, 11 out of 15 recipients were in remission (three out of four UC recipients; 8 out of 11 CD recipients). Generally, bacterial colonization was observed to be lower in CD recipients than in UC recipients at both species and strain levels. Furthermore, across species, different strains displayed disease-specific displacement advantages under two-disease status. Finally, most post-FMT species (> 80%) could be properly predicted (area under the curve > 85%) using a random forest classification model, with the gut microbiota composition and clinical parameters of pre-FMT recipients acting as factors that contribute to prediction accuracy. 10.1002/2211-5463.12744
    Development of Clinical Prediction Models for Surgery and Complications in Crohn's Disease. Guizzetti Leonardo,Zou Guangyong,Khanna Reena,Dulai Parambir S,Sandborn William J,Jairath Vipul,Feagan Brian G Journal of Crohn's & colitis Background and Aims:Crohn's disease-related complications account for a substantial proportion of inflammatory bowel disease-associated health care expenditure. Identifying patients at risk for complications may allow for targeted use of early therapeutic interventions to offset this natural course. We aimed to develop risk prediction models for Crohn's disease-related surgery and complications. Methods:Using data from the Randomised Evaluation of an Algorithm for Crohn's Disease cluster-randomised clinical Trial [REACT], which involved 1898 patients from 40 community practices, separate prediction models were derived and internally validated for predicting Crohn's disease-related surgery and disease-related complications [defined as the first disease-related surgery, hospitalisation, or complication within 24 months]. Model performance was assessed in terms of discrimination and calibration, decision curves, and net benefit analyses. Results:There were 130 [6.8%] disease-related surgeries and 504 [26.6%] complications during the 24-month follow-up period. Selected baseline predictors of surgery included age, gender, disease location, Harvey-Bradshaw Index [HBI] score, stool frequency, antimetabolite or 5-aminosalicylate use, and the presence of a fistula, abscess, or abdominal mass. Selected predictors of complications included those same factors for surgery, plus corticosteroid or anti-tumour necrosis factor use, but excluded 5-aminosalicylate use. Discrimination ability, as measured by validated c-statistics, was 0.70 and 0.62 for the surgery and complication models, respectively. Score charts and nomograms were developed to facilitate future risk score calculation. Conclusions:Separate risk prediction models for Crohn's disease-related surgery and complications were developed using clinical trial data involving community gastroenterology practices. These models could be used to guide Crohn's disease management. External validation is warranted. 10.1093/ecco-jcc/jjx130