Masahiro Takahara

Evaluation of Mucosal Healing in Ulcerative Colitis by Fecal Calprotectin Vs. Fecal Immunochemical Test.

OBJECTIVES:We previously showed that a quantitative fecal immunochemical test (FIT) can predict mucosal healing (MH) in ulcerative colitis (UC). Fecal calprotectin (Fcal) has also been reported as an important biomarker of UC activity. The aim of this study was to compare the predictive ability of these two fecal markers for MH in UC.METHODS:FIT and Fcal were examined in stool samples from consecutive UC patients who underwent colonoscopy. Mucosal status was assessed via the Mayo endoscopic subscore (MES).RESULTS:In total, 105 colonoscopies in 92 UC patients were evaluated in conjunction with the FIT and Fcal results. Both FIT and Fcal results were significantly correlated with MES (Spearman’s rank correlation coefficient: 0.61 and 0.58, respectively). The sensitivity and specificity of the FIT values (<100 ng/ml) for predicting MH (MES 0 alone) were 0.95 and 0.62, respectively, whereas those of Fcal (<250 μg/g) were 0.82 and 0.62, respectively. The sensitivities became similar when MH was defined as MES 0 or 1 (0.86 vs. 0.86). Although the predictability of MH evaluated by the area under the receiver operating characteristics curve was similar for the two fecal markers (FIT 0.83 vs. Fcal 0.82 for MES 0 alone), the FIT results were relatively robust regardless of the cutoff value selected.CONCLUSIONS:Both FIT and Fcal can efficiently predict MH in UC, but FIT appears to be more sensitive than Fcal for predicting MES 0 alone.

Fecal Immunochemical Test Versus Fecal Calprotectin for Prediction of Mucosal Healing in Crohn's Disease

Background:Mucosal healing (MH) has been proposed as a treatment goal of inflammatory bowel disease patients. We reported recently that not only fecal calprotectin (Fcal) but also the fecal immunochemical test (FIT) can predict MH in ulcerative colitis. However, the predictive power of the fecal markers for MH in Crohns disease (CD), particularly with small bowel lesions, has not been reported in detail. The aim of this study was to evaluate the predictability of FIT versus Fcal for MH in CD. Methods:Consecutive CD patients underwent colonoscopy or balloon-assisted enteroscopy according to the disease location. FIT and Fcal were examined using stool samples collected the day before endoscopy. Results:Seventy-one CD patients were analyzed, of whom 42 (59%) underwent balloon-assisted enteroscopy because of the presence of affected lesions in the small intestine. Both the Fcal and the FIT results were significantly correlated with endoscopic activity (r = 0.67 and 0.54, respectively). However, the FIT results did not correlate with the activity in patients with small bowel lesions alone, whereas Fcal did (r = 0.42 versus 0.78). Fcal predicted MH in CD with 87% sensitivity and 71% specificity, whereas the values for FIT were 96% and 48%, respectively. The specificity for MH among patients with small bowel lesions alone was low for FIT (40%) compared with Fcal (80%). Conclusions:Both FIT and Fcal were correlated with the mucosal status of CD. However, the specificity of FIT was not satisfactory, particularly for small bowel lesions.

Large waist circumference is a risk factor for reflux esophagitis in Japanese males.

Background/Aims: The prevalence of reflux esophagitis, which might lead to development of Barrett’s esophagus and esophageal adenocarcinoma, has been increasing. The aim of this study was to assess risk factors for reflux esophagitis. Methods: We conducted a cross-sectional study of 1,495 Japanese subjects undergoing health checkups (822 males and 673 females; median age 50 years) at a tertiary care center. Results: One hundred and twenty-seven subjects (8%) had reflux esophagitis and hiatal hernia was observed in 292 subjects (20%). Reflux esophagitis (13 vs. 3%) and hiatal hernia (28 vs. 9%) were more frequent in males than females. Significant differences in clinical backgrounds were observed between females and males. Multivariate logistic regression analyses revealed that hiatal hernia (OR 6.63, 95% CI 2.47–17.8; p = 0.0002) was associated with reflux esophagitis in females. In males, age (per 1-year increment: OR 0.96, 95% CI 0.94–0.99; p = 0.007), hiatal hernia (OR 3.16, 95% CI 2.05–4.87; p < 0.0001) and waist circumference (per 1-cm increase: OR 1.09, 95% CI 1.02–1.15; p = 0.006) were associated with reflux esophagitis. Conclusions: Abdominal obesity may be an important risk factor for reflux esophagitis in males compared with females.

Ulcerative colitis patients in clinical remission demonstrate correlations between fecal immunochemical test results, mucosal healing, and risk of relapse

AIM To assess the risk of relapse in ulcerative colitis (UC) patients in clinical remission using mucosal status and fecal immunochemical test (FIT) results. METHODS The clinical outcomes of 194 UC patients in clinical remission who underwent colonoscopy were based on evaluations of Mayo endoscopic subscores (MESs) and FIT results. RESULTS Patients with an MES of 0 (n = 94, 48%) showed a ten-fold lower risk of relapse than those with an MES of 1-3 (n = 100, 52%) (HR = 0.10, 95%CI: 0.05-0.19). A negative FIT result (fecal hemoglobin concentrations ≤ 100 ng/mL) was predictive of patients with an MES of 0, with a sensitivity of 0.94 and a specific of 0.76. Moreover, patients with a negative FIT score had a six-fold lower risk of clinical relapse than those with a positive score (HR = 0.17, 95%CI: 0.10-0.28). Inclusion of the distinguishing parameter, sustaining clinical remission > 12 mo, resulted in an even stronger correlation between negative FIT results and an MES of 0 with respect to the risk of clinical relapse (HR = 0.11, 95%CI: 0.04-0.23). CONCLUSION Negative FIT results one year or more after remission induction correlate with complete mucosal healing (MES 0) and better prognosis. Performing FIT one year after remission induction may be useful for evaluating relapse risk.

Consecutive Measurements by Faecal Immunochemical Test in Quiescent Ulcerative Colitis Patients Can Detect Clinical Relapse.

BACKGROUND We have reported that results of the quantitative faecal immunochemical test (FIT; haemoglobin concentrations in faeces measured using an antibody for human haemoglobin) effectively reflect the mucosal status of ulcerative colitis (UC). The aim of this study was to evaluate the predictability of flare-up in quiescent UC patients by consecutive FIT evaluation. METHODS Patients with UC who fulfilled the following criteria by index colonoscopy were enrolled: clinical remission; mucosal healing (Mayo endoscopic subscore 0); and negative FIT (less than 100ng/mL). These patients were followed up prospectively every 1-3 months by monitoring patient symptoms and FIT results between index and subsequent colonoscopies. RESULTS The intervals between 2 colonoscopies (median 2.51 years) of 83 patients (49 males, median age at onset 34 years, median disease duration 9.74 years) were analysed. None of the 43 (52%) patients who maintained negative FIT throughout the observation period exhibited clinical relapse. On the other hand, 25/40 (63%) patients who showed positive conversion of FIT during the period experienced relapse. The cutoff FIT value of 450ng/mL could predict relapse with 73% positive predictive value and 96% negative predictive value. Moreover, positive conversion of FIT preceded occurrence of symptoms by 1 month or more in nearly one-third of patients with relapse. CONCLUSIONS Consecutive measurements of FIT in quiescent UC patients who achieved mucosal healing with negative FIT would help identify patients with clinical relapse whose symptoms had not yet presented. Further investigations are required for more precise prediction of relapse with this modality.

Simultaneous Measurements of Faecal Calprotectin and the Faecal Immunochemical Test in Quiescent Ulcerative Colitis Patients Can Stratify Risk of Relapse

Background Both faecal calprotectin [Fcal] and the faecal immunochemical test [FIT] are useful to predict clinical relapse of ulcerative colitis [UC]. However, the difference between Fcal and FIT in ability to predict relapse has scarcely been reported. Whether the combined use of these two faecal markers increases the predictability is also unknown. Methods UC patients in clinical remission who underwent colonoscopy were enrolled prospectively, and the Fcal and FIT values were examined at enrolment. Their clinical course was observed for 2 years or until relapse. The correlation between the incidence of relapse and the values of the two markers was examined. Results A total of 113 patients were enrolled, and 48 [42%] relapsed. Fcal ≥ 75 μg/g and FIT ≥ 110 ng/mL were defined as Fcal-positive and FIT-positive, respectively, according to the receiver operating characteristic curves. Both Fcal-positive and FIT-positive statuses were independent predictive factors of clinical relapse (hazard ratio [HR] 2.29; 95% confidence interval [CI], 1.23-4.49; p = 0.0086, and HR 2.91; 95% CI, 1.49-5.50; p = 0.0022, respectively). Categorisation of patients into three groups according to the faecal marker status [FIT-positive, FIT-negative and Fcal-positive, and both negative] can efficiently stratify the risk of relapse with graded increases in risk [FIT-negative and Fcal-positive: HR 2.05; 95% CI, 1.02-4.43; p = 0.0045, and FIT-positive: HR 5.43; 95% CI, 2.57-11.76; p < 0.0001, compared with both negative]. Conclusions Fcal vs FIT showed distinct properties regarding the prediction of relapse in UC. A risk assessment using both faecal markers could increase the predictability for relapse.

Efficacy of restarting anti-tumor necrosis factor α agents after surgery in patients with Crohn’s disease

Background/Aims The efficacy of anti-tumor necrosis factor α (anti-TNFα) antibodies for postoperative Crohns disease (CD) in patients who were treated with these agents prior to surgery is largely unknown. Methods CD patients who underwent intestinal resection and received anti-TNFα agents after surgery were divided into 2 groups according to the presence or absence of preoperative anti-TNFα treatment: anti-TNFα restart group or anti-TNFα naïve group. Endoscopic recurrence after surgery was examined according to the preoperative conditions, including administration of anti-TNFα agents before surgery. Results Thirty-six patients received anti-TNFα antibody after surgery: 22 in the anti-TNFα restart group and 14 in the anti-TNFα naïve group. Endoscopic recurrence after surgery was more frequently observed in the anti-TNFα restart group than in the anti-TNFα naïve group (68% vs. 14%, P<0.001). Multivariate analysis revealed the following significant risk factors of endoscopic recurrence after surgery: anti-TNF restart group (odds ratio [OR], 28.10; 95% CI, 3.08–722.00), age at diagnosis <23 years (OR, 24.30; 95% CI, 1.67–1,312.00), serum albumin concentration at surgery <3.3 g/dL (OR, 34.10; 95% CI, 1.72–2,804.00), and presence of inflammation outside of the surgical site (OR, 21.40; 95% CI, 1.02–2,150.00). Treatment intensification for patients with endoscopic recurrence in the anti-TNFα restart group showed limited responses, with only 1 of 12 patients achieving endoscopic remission. Conclusions The efficacy of restarting anti-TNFα antibody treatment after surgery was limited, and treatment intensification or a change to different classes of biologics should be considered for those patients.

Acute Appendicitis Caused by Previous Endoscopic Submucosal Dissection for an Adenoma Adjacent to the Appendiceal Orifice

Endoscopic submucosal dissection (ESD) is a groundbreaking treatment for tumors adjacent to the appendiceal orifice that are difficult to remove by conventional endoscopic mucosal resection, and successful cases are increasingly reported. However, little is known about the subsequent complications, especially long-term complications. A female in her early 70s with a 15-mm cecal tumor adjacent to the appendiceal orifice – discovered incidentally during a screening colonoscopy – underwent hybrid ESD of the lesion. We completely resected the tumor, and she was discharged 5 days later with a pathological diagnosis of high-grade tubular adenoma. Ten months postoperatively, she experienced sudden-onset right lower quadrant pain and was diagnosed with acute appendicitis at another hospital. Due to suspicion that her condition was the result of residual tumor, her surgeon performed an emergency laparoscopic cecectomy. The pathological examination of the resected specimen showed thick scarring adjacent to the appendiceal orifice and no residual tumor. The previous ESD was identified as the cause of the scar, and the scar was the only finding to account for the patient’s appendicitis. This case is significant because the patient required additional surgery due to a complication of ESD. Further, it indicates that acute appendicitis may be a late complication of submucosal dissection near the appendiceal orifice. As ESD becomes more widely used, it is likely that more cecal tumors will be treated endoscopically. It is important to be aware of the late complications of ESD for these tumors.

Retention of patency capsule in a patient with Crohn's disease

A 40-year-old Japanese man with abdominal pain was referred to our hospital. The patient had been diagnosed with Crohns disease at the age of 21 years and had since then received treatment with mesalazine and had been advocated an elemental diet. About 30 months before his visit to the hospital, he had swallowed a patency capsule, the retention of which in the ileum was subsequently detected on abdominal ultrasonography. The patient was advised to undergo the evaluation of stenosis, but he refused further investigation at that time. Computed tomography scanning performed at our institution revealed stenosis of the ileum and the presence of a high-density material in the proximal side of the stenosis. Double-balloon enteroscopy and enterography with contrast media revealed multiple stenoses of the ileum. The stenotic ileum was surgically resected, and a foreign body was removed. Electron microscopy analysis revealed that the foreign body was the cellophane wall of the PillCamTM patency capsule. Thus, the retention of the cellophane wall of a patency capsule after consumption was diagnosed for the current case on the basis of the study findings.

NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study

BackgroundDespite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.MethodsOverall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.ResultsWe confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E−63, 1.32E−69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E−04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively).ConclusionsGenotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.