Trough level of infliximab is useful for assessing mucosal healing in Crohn's disease: a prospective cohort study.

BACKGROUND/AIMS: Decreased trough levels of infliximab (TLI) and antibodies to infliximab (ATI) are associated with loss of response (LOR) in Crohn's disease. Two prospective studies were conducted to determine whether TLI or ATI better correlates with LOR (Study 1), and whether TLI could become a predictor of mucosal healing (MH) (Study 2). METHODS: Study 1 was conducted in 108 patients, including those with LOR and remission to compare ATI and TLI in discriminating the 2 conditions based on receiver operating characteristic (ROC) curve analyses. Study 2 involved 35 patients who were evaluated endoscopically. RESULTS: In Study 1, there were no differences between the 2 assays in ROC curve analyses; the TLI cutoff value for LOR was 2.6 µg/mL (sensitivity, 70.9%; specificity, 79.2%), and the ATI cutoff value was 4.9 µg/mL (sensitivity, 65.5%; specificity, 67.9%). The AUROC (area under the ROC curve) of TLI was greater than that of ATI. AUROC was useful for discriminating between the 2 conditions. In Study 2, the TLI was significantly higher in the colonic MH group than in the non-MH group (2.7 µg/mL vs. 0.5 µg/mL, P=0.032). CONCLUSIONS: TLI is better than ATI for clinically diagnosing LOR, and a correlation was observed between TLI and colonic MH.

Long-term course of Crohn's disease in Japan: Incidence of complications, cumulative rate of initial surgery, and risk factors at diagnosis for initial surgery.

BACKGROUND AND AIMS: Intestinal complications of stenosis or fistula may occur during the course of Crohn's disease (CD), and surgery is performed in a fair number of patients. The risk factors for initial surgery in a Japanese hospital-based cohort of CD patients were evaluated. METHODS: This study was a single-center, retrospective, cohort study. The subjects were 520 patients who underwent inpatient and outpatient treatment at our hospital, had a definitive diagnosis of CD, and no previous surgery. Three parameters were investigated: (i) cumulative incidence of stenosis and fistula; (ii) cumulative rate of initial surgery for each disease type; and (iii) risk factors at diagnosis for initial surgery. RESULTS: (i) Stenosis and fistula increased with time, with stenosis or fistula appearing in about half of the patients after 5 years. (ii) The cumulative rate of initial surgery was about 50% after 10 years. (iii) The patient factors at diagnosis of current smoker, upper gastrointestinal disease, stricturing, penetrating, moderate to severe stenosis of the jejunum, moderate to severe stenosis of the ileum, and moderate to severe stenosis of the terminal ileum were risk factors for initial surgery. CONCLUSIONS: Stenosis or fistula appeared in about half of the patients after 5 years from diagnosis. When upper gastrointestinal disease or complicated small intestinal lesions are seen at the time of diagnosis, the cumulative rate of initial surgery is significantly higher.

Mucosal healing of ileal lesions is associated with long-term clinical remission after infliximab maintenance treatment in patients with Crohn's disease.

BACKGROUND AND AIM: The aim of the present study was to endoscopically evaluate ileal mucosal healing during maintenance therapy with infliximab in order to investigate the clinical significance of endoscopic examination of ileal lesions in Crohn's disease patients. METHODS: This study retrospectively analyzed 54 patients who mainly had active ulcers of the ileum on endoscopy at baseline who were responsive to infliximab induction and who received infliximab maintenance therapy. Mucosal healing was defined as no ulcer or only ulcer scar. At the time of follow-up endoscopy after starting infliximab, endoscopic score, mucosal healing, and clinical remission were evaluated. On long-term follow up, correlations between mucosal healing and long-term clinical remission, and between mucosal healing and the need for major abdominal surgery, were also evaluated. RESULTS: Ileal mucosal healing and complete mucosal healing were significantly correlated with clinical remission (P = 0.046, P = 0.0001, respectively). The rate of long-term clinical remission was significantly higher in patients with complete mucosal healing (P = 0.025). The rate of major abdominal surgery for strictures was significantly lower in patients with complete mucosal healing (P = 0.044). CONCLUSIONS: Complete mucosal healing after 1-2 years was a predictive factor for long-term clinical remission up to 4 years after starting infliximab. A lack of complete mucosal healing was a predictive factor for major abdominal surgery for strictures. The present study suggests that endoscopic evaluation of ileal lesions is useful for long-term prognosis of Crohn's disease patients.

Long-term outcome of endoscopic balloon dilation for small bowel strictures in patients with Crohn's disease.

BACKGROUND AND AIM: Endoscopic balloon dilation (EBD) is an alternative to surgery for small bowel strictures of patients with Crohn's disease (CD). However, little is known about the long-term efficacy of EBD. The aim of the present study was to clarify the long-term outcome of EBD for small bowel strictures in patients with CD. METHODS: Subjects comprised 65 patients with CD who underwent EBD for small intestinal strictures and were followed up for at least 6 months. All subjects had obstructive symptoms as a result of small bowel strictures. Short-term success was defined as technical success and the disappearance of obstructive symptoms. The short-term success rate of EBD, its safety profile, the cumulative surgery-free rate and the cumulative redilation-free rate were investigated. RESULTS: Short-term success rate was 80.0% (52/65). Complications were encountered in six of the 65 patients (9.2%). Seventeen patients (26.2%) underwent surgery during the observation period of this study. Cumulative surgery-free rate after initial EBD was 79% at 2 years and 73% at 3 years, respectively. EBD successful cases showed significantly higher surgery-free rates than unsuccessful cases (P < 0.0001). In 52 of the successful cases, the cumulative redilation-free rate after initial EBD was 64% at 2 years and 47% at 3 years, respectively. CONCLUSION: EBD for small bowel strictures secondary to CD provides not only short-term success but also long-term efficacy. However, the high redilation rate is one of the clinical problems of this procedure.

Two patients with new granulomatous lung lesions during treatment of Crohn's disease.

Two patients with granulomatous lung lesions thought to be related to Crohn's disease (CD) are reported. Patient 1 was a 43-year-old man who was diagnosed with CD at age 11 years. He developed a fever in the 38 °C, and a chest X-ray and CT scan showed infiltrates with air bronchograms in the right upper lobe and left lingular segment. Transbronchial lung biopsy (TBLB) revealed granulomatous lesions. Patient 2 was a 76-year-old woman who was diagnosed with CD at age 44 years. Chest CT showed infiltrates and nodular shadows in both lung fields. Video-assisted thoracoscopic surgery (VATS) in June 2012 revealed granulomatous lesions. Tuberculosis, fungal infections, drug-induced lung disorder, and sarcoidosis were ruled out as a cause of the granulomatous lesions in both patients. The aetiology was thought to be CD.

Incidence, clinical characteristics, long-term course, and comparison of progressive and nonprogressive cases of aphthous-type Crohn's disease: a single-center cohort study.

BACKGROUND/AIMS: In Japan, aphthous-type Crohn's disease (type A CD) is thought to represent an early phase of Crohn's disease (CD), and diagnosis of type A CD is possible in the diagnostic criteria for CD in Japan. However, the details of type A CD are not well understood. METHODS: Subjects comprised 649 CD patients diagnosed between 1985 and 2011. The incidence of type A CD over time was clarified in two periods (1985-2004 and 2005-2011). The course of type A CD was also investigated, and cases that did and did not progress to typical CD were compared. RESULTS: No significant difference was seen in the incidence of type A CD between the two periods (5.2 vs. 8.5%, p = 0.125). Type A CD patients followed at our hospital progressed to typical CD at a rate of 59.3%. In comparing progressive and nonprogressive cases, the frequency of large, densely distributed aphthous lesions in the small intestine was higher among progressive cases (p = 0.018). CONCLUSION: Type A CD is an early phase of CD, and CD diagnostic criteria including early cases are valid in Japan.

Magnifying endoscopy with narrow-band imaging is useful in the differential diagnosis between low-grade adenoma and early cancer of superficial elevated gastric lesions.

BACKGROUND: The usefulness of magnifying gastroscopy has been reported in differentiating between benign and malignant gastric mucosal lesions. However, there have been no studies of the usefulness of magnifying endoscopy with narrow-band imaging (M-NBI) in the diagnosis of superficial (non-polypoid) elevated lesions of the stomach. In this study, we investigated the ability of M-NBI to differentiate between cancer and adenoma in superficial elevated lesions of the stomach. METHODS: We examined 93 consecutive superficial elevated lesions of the stomach. We defined the endoscopic criteria for early cancer as red coloring using conventional white light imaging (C-WLI), and an irregular microvascular pattern with a demarcation line, or irregular microsurface pattern with a demarcation line, using M-NBI. We determined the sensitivity, specificity and accuracy of C-WLI and M-NBI in the diagnosis of these 93 lesions. RESULTS: The sensitivity, specificity, and accuracy (95 % confidence interval) of C-WLI versus M-NBI were 64 % (52-76 %) versus 95 % (90-100 %), 94 % (86-100 %) versus 88 % (77-99 %), and 74 % (66-83 %) versus 92 % (86-98 %), respectively. Sensitivity and accuracy were significantly higher for M-NBI than C-WLI. CONCLUSIONS: M-NBI appears to be useful in differentiating between cancerous and adenomatous superficial elevated lesions of the stomach.

Validity of the usefulness of microvascular architecture and microsurface structure using magnifying endoscopy with narrow-band imaging in the colorectal neoplasm.

BACKGROUND: Magnifying endoscopy (ME) with narrow-band imaging (NBI) has been described as useful in diagnosing colorectal neoplasms. However, there is no standardized simple classification system, and its usefulness in comparison with pit pattern diagnosis by magnifying chromoendoscopy (MC) is unclear. The aim of this study was to investigate the usefulness of evaluations of microvascular architecture (MV) and microsurface structure (MS) by ME with NBI in the diagnosis of colorectal neoplasms. METHODS: A total of 360 colorectal neoplasms were analyzed by retrospective analysis of prospectively collected data. The vessel plus surface (VS) classification system was applied for ME with NBI diagnosis. The main outcome measurement was comparison of the diagnostic performance of ME with NBI and MC. RESULTS: The sensitivity of ME with NBI and MC for the diagnosis of adenomas was 91.9% and 95.7%, respectively, and their specificity was 79.2% and 79.9%, respectively. The sensitivity of ME with NBI and MC for the diagnosis of cancer was 70.5% and 79.9%, respectively, and the specificity was 95.3% and 95.7%, respectively. The sensitivity of ME with NBI and MC for the diagnosis of cancer with deep submucosal invasion was 50.0% and 88.0%, respectively (P < 0.0001), and their specificity was 100% and 82.8%, respectively (P < 0.0001). CONCLUSIONS: The specificity of evaluation of MV and MS by ME with NBI for the diagnosis of cancer with deep submucosal invasion was much higher than that of pit pattern analysis by MC.

Value of concomitant endoscopic balloon dilation for intestinal stricture during long-term infliximab therapy in patients with Crohn's disease.

AIM: We assessed the long-term outcome of infliximab (IFX) therapy in patients with Crohn's disease (CD) and investigated the efficacy of concomitant endoscopic balloon dilation (EBD) for intestinal stricture during treatment. METHODS: The effectiveness of maintenance therapy with IFX was retrospectively evaluated in 185 patients with CD in a single center (median observation period 24 months). IFX effectiveness with and without immunomodulators (IMM) and enteral nutrition (EN), as well as cumulative surgery-free rates, were compared. The efficacy of concomitant EBD in patients with obstructive symptoms and high-level stricture was evaluated. RESULTS: In 185 patients receiving the maintenance therapy, the long-term efficacy rate was 84.9% at 24 months and 79.0% at 48 months. The cumulative surgery-free rate was significantly higher in the maintenance group (P < 0.001). Concomitant IMM and EN did not significantly affect the effectiveness of IFX. IFX was discontinued in only 18 cases (7.3%). Symptomatic high-level stricture occurred in 33 patients (17.8%) in the maintenance group and the cumulative surgery-free rate was significantly higher in the EBD combination compared with the non-EBD group (P < 0.05). If EBD were considered invasive intervention, the actual cumulative surgery rate in the maintenance group was significantly lower compared with the cumulative invasive intervention rate (P < 0.001). CONCLUSION: Long-term treatment with IFX is highly effective. The surgery-free rate was clearly higher in the maintenance group. Only concomitant EBD for intestinal stricture helped in the avoidance of surgery.

Clinical and endoscopic features of amyloidosis secondary to Crohn's disease: diagnostic value of duodenal observation and biopsy.

AIM: Recent reports have focused on the development of secondary amyloidosis (AMY) as a complication of Crohn's disease (CD). The present study was carried out to investigate the frequency of AMY secondary to CD, its clinical and endoscopic features, and the importance of duodenal biopsy in detecting this disease. METHODS: This study involved 408 patients diagnosed with CD who were endoscopically and histologically examined at our hospital. At follow up, we analyzed the incidence of AMY complications, the clinical features of AMY and the methods to diagnose AMY. RESULTS: The incidence of AMY was 2.5% (10/408). The disease type at the time of CD diagnosis was small and large bowel type (SL) in eight patients, small bowel type in one and large bowel type in one. The incidence of AMY was significantly higher in patients with SL than in patients with other disease types. The length of time from onset of CD to diagnosis of AMY was 14.1 ± 8.0 years. The cumulative incidence of AMY was 1.0% at 10 years and 5.7% at 20 years after onset. In terms of the method used to diagnose AMY, the positive rate of AMY diagnosis was 100% with endoscopic duodenal biopsy. CONCLUSION: The incidence of AMY as a complication of CD was low (2.5%). However, because this complication adversely affects patients' prognoses, it is important to check for the presence of AMY, particularly in the duodenum, in patients for whom more than 10 years have elapsed since the development of CD.

Carbon dioxide insufflation compared with air insufflation in double-balloon enteroscopy: a prospective, randomized, double-blind trial.

BACKGROUND: Few studies have evaluated the degree of pain, the amount of retained gas, and the safety of carbon dioxide (CO(2)) insufflation in patients undergoing double-balloon enteroscopy (DBE). OBJECTIVE: To clarify the usefulness and safety of CO(2) insufflation during DBE. DESIGN: Single-center, prospective, randomized, double-blind, controlled trial. SETTING: University hospital. PATIENTS: Forty eligible patients with small-bowel disease for whom DBE was indicated were randomized to a CO(2) insufflation (CO(2)) group or an air insufflation (air) group by means of sealed envelopes. INTERVENTION: DBE with insufflation of CO(2) or air. MAIN OUTCOME MEASUREMENTS: Efficacy evaluation was based on the degree of pain as assessed by use of a visual analog scale (VAS) and the amount of residual gas retention within the small and large bowels on radiography. The safety of CO(2) insufflation was evaluated by arterial blood gas analysis. RESULTS: Significantly fewer patients in the CO(2) group had severe pain of ≥ 50 mm on the VAS during DBE than in the air group (P = .02). Significantly less gas was retained in the small bowel just after and at 3 hours after DBE in the CO(2) group than in the air group (P = .003, P = .01, respectively). There was significantly less residual gas retention in the large bowel at 3 hours after DBE in the CO(2) group than in the air group (P = .02). There was no significant difference in pre-DBE and post-DBE partial pressure of oxygen in the blood (PaO(2)) and partial pressure of carbon dioxide in the blood (PaCO(2)) between groups. LIMITATIONS: Small sample size. CONCLUSION: CO(2) insufflation is a safe and useful procedure when performed during DBE.

Endoscopic balloon dilatation using double-balloon endoscopy is a useful and safe treatment for small intestinal strictures in Crohn's disease.

BACKGROUND: Endoscopic balloon dilatation (EBD) is a therapeutic option for intestinal strictures of Crohn's disease (CD). Double-balloon endoscopy (DBE) enables EBD to be performed even for deep-situated strictures of the small intestine. The aim of this study was to clarify the efficacy and safety of EBD using DBE for small bowel strictures in patients with CD. PATIENTS AND METHODS: The subjects comprised 25 patients with CD who underwent EBD using DBE for small intestinal strictures for which a colonoscope or gastrointestinal scope could not be inserted. All subjects had obstructive symptoms due to strictures that were confirmed using small intestinal enteroclysis. They were observed for at least 6 months after the initial EBD. The short-term success rate of EBD using DBE, the complication rate and the long-term outcome were investigated. RESULTS: This procedure was successful with regard to short-term dilatation in 18 of the 25 CD patients (72%). Long strictures measuring more than 3 cm were seen in six out of seven (85.7%) of the unsuccessful EBD cases, compared with two out of 18 (11.1%) of the successful EBD cases (P=0.001). Complications were encountered in two of the 25 patients (8%). The cumulative surgery-free rate for all the subjects was 83% and 72% at 6 and 12 months, respectively. CONCLUSION: EBD using DBE is a useful and safe procedure for small intestinal short strictures in CD patients. We conclude that this procedure is a therapeutic option that should be attempted before resorting to surgical therapy.

Efficacy of azathioprine in mild or moderate relapse in Crohn's disease: clinical and endoscopic evaluation.

AIM: The present study was aimed at evaluating the efficacy of azathioprine (AZA) in patients with active and relapsing Crohn's disease (CD) and the usefulness of endoscopy in this evaluation. METHODS: The 53 patients with active CD treated with AZA at our hospital were subjected to the following retrospective analysis: (i) evaluation of the clinical efficacy of AZA through comparison of the Crohn's disease activity index (CDAI); (ii) analysis of the relationship of the clinical efficacy to the difference in the mean corpuscular volume (MCV); (iii) evaluation of mucosal healing through analysis of the scores of the endoscopic findings in 16 patients; and (iv) analysis of the relapse rate. RESULTS: (i) Among the 53 patients, treatment was rated as having induced complete remission in 22.6%, as being effective in 41.5%, and as being ineffective in 13.3% of patients. The treatment was discontinued in 22.6% of patients. (ii) The post-treatment MCV was significantly increased after treatment. (iii) When the ulcer score estimated after treatment was compared with that before the start of treatment, a significant improvement of the score was noted. (iv) When the non-relapse rate after AZA therapy was calculated in the 41 patients followed up for 12 months, it was 84.8%. CONCLUSION: AZA was shown to cause endoscopic mucosal healing as well as clinical efficacy. In the present study, it was inferred that the efficacy of AZA therapy in CD patients is manifested clinically first and that mucosal healing is an effect that occurs later.

Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease.

BACKGROUND AND AIMS: Azathioprine (AZA) is associated with a high frequency of adverse reactions. We examined polymorphism of the thiopurine S-methyltransferase (TPMT) gene to determine whether the TPMT genotype would be a predictive marker for the development of adverse reactions to AZA. METHODS: The frequency of TPMT mutations was investigated in 147 Japanese inflammatory bowel disease (IBD) patients retrospectively. In these subjects, the presence of four mutant alleles (TPMT*2, *3B, *3C and *8) was determined by direct sequencing. The incidence of adverse reactions among patients carrying wild-type TPMT was investigated. The blood level of 6-thioguanine nucleotide (6-TGN) was measured and analyzed in 47 patients with wild-type TPMT. The results were analyzed in relation to the concomitant use of aminosalicylates (ASA). RESULTS: Of the 147 patients, 144 (98.0%) were wild-type for TPMT (TPMT*1/*1) and three (2.0%) carried a mutant TPMT allele (TPMT*1/*3C). The incidence of adverse reactions was 33.3% (38/114) in the wild-type group. Leukopenia (WBC < or = 3000/microL) was seen in 15.8% of the patients with wild-type TPMT. 6-TGN levels varied among 47 patients with wild-type TPMT. The blood levels of 6-TGN were significantly higher in the patients receiving concomitant ASA treatment compared with those not receiving concomitant ASA treatment (P = 0.0033). CONCLUSION: The frequency of TPMT gene mutations is low among Japanese IBD patients. The incidence of adverse reactions to AZA was high, even in patients carrying wild-type TPMT. It is concluded that determination of TPMT genotype may not be useful in Japanese IBD patients to predict adverse reactions to AZA.

Differentiating enterocutaneous fistulae from suture abscesses complicating Crohn's disease using oral administration of indocyanine green.

BACKGROUND AND AIM: Clinicians encounter difficulties distinguishing enterocutaneous fistulae from postoperative suture abscesses solely by diagnostic imaging in patients with Crohn's disease. The aim of this study was to examine whether use of intraintestinal administration of indocyanine green (ICG) could differentiate the conditions. METHODS: Twenty-four patients with Crohn's disease and a possible enterocutaneous fistula at the abdominal wall based on manifestations of pus drainage and exudate were enrolled. A positive test was defined by macroscopic confirmation of staining by ICG dye, which had been administered orally, on the gauze dressing applied to the lesion site. RESULTS: Positive responses occurred in 16 of the 24 patients. In 13 of the 16 positive patients, a fistulous communication between the lesion and the gastrointestinal tract was documented by either surgery or X-ray examination. In the remaining three, fistulae were completely closed after administration of infliximab. The positive predictive value of the oral ICG test was 16/16 (100%). Six of the eight negative oral ICG test patients (75%) had subcutaneous (silk-suture) abscesses that were easily closed following fistulotomy. The other two patients had fistulas confirmed either by surgery or fistulography, indicating a false negative response from the oral ICG test. The negative predictive value of the oral ICG test was 6/8 (75%); thus, the ability of the oral ICG test to correctly diagnose was 22/24 (92%). CONCLUSIONS: This oral ICG test offers a suitable methodology for those patients possessing an occult fistulous lesion at an early stage, and where a differential diagnosis is difficult using diagnostic imaging.

Three-dimensional computed tomography pancreatography of an annular pancreas with special reference to embryogenesis.

OBJECTIVES: Several hypotheses have been proposed to explain the embryogenesis of an annular pancreas. Three-dimensional (3D) imaging of the annular pancreas may be useful to elucidate the embryogenesis. The aim of this case report is to clarify the pancreatic ducts in the annular pancreas by 3D computed tomography pancreatography (3D-CTP), stereographically. METHODS: Three-dimensional CTP under endoscopic retrograde pancreatography using a balloon catheter was performed with a helical CT scanner. Three-dimensional images of the pancreatic duct were obtained with simple threshold, shaped surface display. RESULTS: Wirsung duct that surrounds the ventral side of the descending portion of the duodenum and Santorini duct that surrounds the dorsal side of the descending portion of the duodenum were reconstructed by 3D-CTP, stereographically, and the presence of an annular pancreas was confirmed. These findings suggest that the formation of the annular pancreas in the current case may be attributable not only to abnormal development of the right lobe of the ventral pancreatic bud, but also to overgrowth of the dorsal pancreatic bud toward the ventral aspect of the duodenum or excessive rotation of the duodenum following fusion of the ventral bud to the dorsal bud. CONCLUSION: Three-dimensional CTP is expected to contribute usefully toward clarifying the embryogenesis of an annular pancreas.