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1.
Medicine (Baltimore) ; 100(29): e26550, 2021 Jul 23.
Article En | MEDLINE | ID: mdl-34398010

ABSTRACT: The Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) was recently reported as a new scoring system to evaluate the mucosal lesions of patients with Crohn's disease (CD). We investigated whether CECDAI is useful for assessing the necessity of early additional treatment in patients with CD in clinical remission.Twenty-one patients with small intestinal CD in clinical remission underwent capsule endoscopy (CE). The CECDAI and Lewis score (LS) were used to evaluate the intestinal lesions. We analyzed the correlations between several biomarkers and CECDAI or LS and examined the changes in therapeutic regimens based on the CECDAI.CE identified intestinal abnormalities in most CD patients in clinical remission: 81.0% and 85.7%, as assessed using CECDAI and LS, respectively. A significant positive correlation was observed between the CDAI and LS (P = .025), as well as between CDAI and CECDAI (P = .014) in these cases. Compared to LS, CECDAI scores were more evenly distributed. No significant correlations were observed between endoscopic scores and serum markers, including CRP, hemoglobin, and albumin levels. Additional treatment was performed significantly more often in patients with moderate-severe disease activity (CECDAI ≥5.8) (P = .012) than in those with normal (CECDAI <3.5) and mild (3.5≤CECDAI<5.8) disease activity. Resection of the small intestine did not affect the small bowel transit time or CE score.CECDAI is useful in evaluating mucosal lesions in small bowel CD patients in clinical remission and helps in assessing the requirement for additional treatment for these patients, including those who undergo intestinal resection.


Capsule Endoscopy/methods , Crohn Disease/diagnostic imaging , Adolescent , Adult , Aged , Biomarkers/analysis , Biomarkers/blood , Capsule Endoscopy/statistics & numerical data , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Severity of Illness Index , Statistics, Nonparametric
2.
PLoS One ; 16(7): e0254548, 2021.
Article En | MEDLINE | ID: mdl-34242369

Adalimumab (ADA) trough level and anti-ADA antibody (AAA) positivity influence mucosal healing and loss of response in patients with inflammatory bowel disease (IBD). In this study, we clarified the correlation between ADA monitoring, including non-trough level, and real-world IBD clinical outcomes. This retrospective, observational, single-center study involved patients with ulcerative colitis (19) and Crohn's disease (33) treated with ADA from January 2007 to August 2018. Serum ADA and AAA levels were measured 4‒14 days after ADA administration. The AAA positivity rate was 23.1% (12/52). ADA continuity was higher in AAA-negative patients than in AAA-positive patients (P = 0.223). Receiver operating characteristic (ROC) analysis revealed that a serum AAA cut-off of 9.2 µg/mL was associated with ADA continuity. The ADA level was significantly higher in the endoscopic remission group than in the non-remission group (P = 0.02). Based on the ROC curve analysis results of serum ADA level and endoscopic remission, the cut-off value of the serum ADA level was set to 11.1 µg/mL. Under the combined use of ADA with immunomodulators and AAA positivity, ADA continuity was significantly higher when the serum AAA level at 4-14 days after ADA administration was ≥9.2 µg/mL. Furthermore, endoscopic remission can be expected with a serum ADA level of ≥11.1 µg/mL. Overall, to predict clinical outcomes, it would be useful to measure the blood level of ADA regardless of the timing of the trough.


Adalimumab/pharmacokinetics , Inflammatory Bowel Diseases/drug therapy , Adalimumab/blood , Adalimumab/therapeutic use , Colitis, Ulcerative/blood , Colitis, Ulcerative/drug therapy , Crohn Disease/blood , Crohn Disease/drug therapy , Humans , Inflammatory Bowel Diseases/blood , ROC Curve , Retrospective Studies
3.
J Crohns Colitis ; 14(12): 1693-1701, 2020 Dec 02.
Article En | MEDLINE | ID: mdl-32412598

BACKGROUND & AIMS: The new curcumin derivative Theracurmin® has a 27-fold higher absorption rate than natural curcumin powder. Theracurmin® is an inhibitor of nuclear factor-κB, which mediates the expression of inflammatory cytokines. The effect of Theracurmin® on inflammatory bowel disease in humans has not been explored; therefore, we investigated the efficacy and safety of Theracurmin® in patients with Crohn's disease. METHODS: In this randomized, double-blinded study performed at 5 independent medical centers in Japan, Theracurmin® (360 mg/day, n = 20) or placebo (n = 10) was administered to patients with active mild-to-moderate Crohn's disease for 12 weeks. The agent's efficacy was assessed by evaluating clinical and endoscopic remission, healing of anal lesions, and blood levels of inflammatory markers. RESULTS: In the Theracurmin® group, a significant reduction in clinical disease activity was observed in week 12 relative to that in week 0 (p = 0.005). On intention-to-treat analysis, clinical remission rates were 35%, 40%, and 40% at weeks 4, 8, and 12, respectively, which were significantly higher than those in the placebo group (all 0%; p = 0.033, p = 0.020, and p = 0.020, respectively). Furthermore, reduction in endoscopic Crohn's disease severity (p = 0.032) was observed at week 12 in the Theracurmin® group. The endoscopic remission rates were 15% and 0% in the Theracurmin® and placebo groups, respectively. Significant healing of anal lesions (p = 0.017) was observed at week 8 in the Theracurmin® group. No serious adverse events were observed in either group throughout the study. CONCLUSIONS: Theracurmin® shows significant clinical and endoscopic efficacy together with a favorable safety profile in patients with active mild-to-moderate Crohn's disease. CLINICAL TRIAL UMIN REGISTRATION ID: UMIN000015770.


Crohn Disease/drug therapy , Curcumin/pharmacology , Adult , Aged , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Crohn Disease/physiopathology , Curcumin/therapeutic use , Double-Blind Method , Female , Humans , Japan , Male , Middle Aged
4.
Int J Colorectal Dis ; 35(9): 1729-1739, 2020 Sep.
Article En | MEDLINE | ID: mdl-32472230

PURPOSE: The effects of ulcerative colitis (UC) duration on biomarker accuracy are unknown. We investigated the effects of UC duration on the predictive accuracy of biomarkers including immunochemical fecal occult blood test (FOBT, also known as FIT), prostaglandin E-major urinary metabolite (PGE-MUM), and C-reactive protein (CRP). METHODS: We divided 133 samples into groups based on disease duration. Clinical and endoscopic remission was defined as Lichtiger's clinical activity index (CAI) of ≤ 4, Mayo endoscopic subscore (MES) of 0, and UC endoscopic index of severity (UCEIS) of ≤ 1. RESULTS: FIT results were significantly correlated with all activity scores when the disease duration was < 4 years. When the disease duration was ≥ 4 years, FIT results were significantly correlated with the CAI and MES but not with UCEIS. When the disease duration was ≥ 5 years, FIT and CAI were significantly correlated, whereas FIT and MES or FIT and UCEIS did not show any correlation. When the duration was ≥ 4 years, PGE-MUM and CRP showed a significant correlation with CAI, MES, and UCEIS. Receiver operating characteristic curve analysis of biomarker data for predicting endoscopic remission showed that the accuracy of FIT was superior to that of PGE-MUM and CRP in the < 4-year group. CONCLUSIONS: FIT is an accurate biomarker reflecting the endoscopic score until 4 years in patients with UC. However, owing to the increased number of false negatives, the usefulness of FIT may decline after 4 years. Hence, evaluation of UC in combination with other biomarkers is recommended.


Colitis, Ulcerative , Biomarkers , Colitis, Ulcerative/diagnosis , Colonoscopy , Feces/chemistry , Humans , Intestinal Mucosa/chemistry , Leukocyte L1 Antigen Complex , Occult Blood , Severity of Illness Index
5.
BMC Gastroenterol ; 20(1): 114, 2020 Apr 19.
Article En | MEDLINE | ID: mdl-32306914

BACKGROUND: Prostaglandin E-major urinary metabolite (PGE-MUM) may be a novel biomarker for evaluating disease activity in ulcerative colitis (UC). We compared its usefulness to that of the fecal immunochemical occult blood test (FIT). METHODS: PGE-MUM and FIT measurements were performed of 92 urinary and fecal samples obtained from 60 patients with UC. Endoscopic activity was determined by Mayo endoscopic subscore (eMayo) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score. RESULTS: PGE-MUM levels and FIT results showed a significant correlation with respect to eMayo (P <  0.001 and P < 0.001, respectively), and there was a significant difference in PGE-MUM values between the groups below eMayo1 and above eMayo2 (P = 0.012). Both biomarkers were significantly correlated with the UCEIS score (P < 0.001 and P < 0.001, respectively), and the PGE-MUM values were significantly different between groups below UCEIS1 and above UCEIS2 (P = 0.012). PGE-MUM and FIT were significantly correlated with eMayo in the group with a disease duration < 5 years (P = 0.041 and P < 0.001, respectively). Although PGE-MUM and eMayo differed significantly between groups over 5 years (P = 0.012), FIT was not correlated with eMayo (P = 0.101). CONCLUSIONS: PGE-MUM is useful as a biomarker as FIT for evaluating the endoscopic activity, particularly in long-term affected patients with UC.


Colitis, Ulcerative/diagnostic imaging , Colitis, Ulcerative/urine , Occult Blood , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/analysis , Biomarkers/blood , Biomarkers/urine , Blood Sedimentation , C-Reactive Protein/metabolism , Colonoscopy , Dinoprostone/metabolism , Female , Humans , Male , Middle Aged , ROC Curve , Serum Albumin/metabolism , Severity of Illness Index , Time Factors , Young Adult
6.
Dig Dis ; 37(1): 11-20, 2019.
Article En | MEDLINE | ID: mdl-30205400

BACKGROUND: Although evidence for the short- to medium-term efficacy of adalimumab in ulcerative colitis (UC) patients is emerging, there are a limited number of reports on the long-term efficacy of adalimumab. This study was to understand baseline demographic features, which potentially could be risk factors for relapse or colectomy following induction of remission by adalimumab in UC patients. Additionally, factors affecting long-term outcomes were to be identified. METHODS: Twenty-one patients with UC who had been treated with adalimumab were reviewed retrospectively. Comparative analyses were undertaken by factoring steroid withdrawal versus non-withdrawal, long-term remission versus relapse following remission, and requiring surgical intervention for UC versus surgery-free. RESULTS: Adalimumab treatment was associated with steroid tapering in steroid-dependent cases in the long term. Of the 14 patients in whom clinical remission was achieved, the cumulative nonrelapse survival rate at 350 weeks was 43.8% and the cumulative nonoperative survival rate was 85.7%. Risk factors for surgery included intolerance to salicylates (p = 0.005) and past treatment with tacrolimus (p = 0.023). CONCLUSIONS: Adalimumab treatment was associated with long-term efficacy in patients with mild UC - patients achieved a high cumulative nonoperative survival rate over a long period of time, beyond 6 years.


Adalimumab/adverse effects , Adalimumab/therapeutic use , Colitis, Ulcerative/drug therapy , Practice Patterns, Physicians' , Adolescent , Adult , Aged , C-Reactive Protein/metabolism , Colectomy , Colitis, Ulcerative/surgery , Female , Humans , Infliximab/therapeutic use , Kaplan-Meier Estimate , Male , Middle Aged , Retrospective Studies , Risk Factors , Serum Albumin/metabolism , Steroids/therapeutic use , Tacrolimus/therapeutic use , Time Factors , Treatment Outcome , Young Adult
7.
World J Clin Cases ; 6(15): 952-960, 2018 Dec 06.
Article En | MEDLINE | ID: mdl-30568951

AIM: To examine whether second generation of colon capsule endoscopy (CCE-2) is acceptable for assessing the severity of mucosal inflammation and evaluating mucosal healing using CCE-2 is able to predict outcome in ulcerative colitis (UC) patients, especially in clinical remission. METHODS: A total of 30 consecutive UC patients in clinical remission were enrolled to undergo CCE-2. Clinical remission was defined as clinical activity index (CAI) ≤ 4 according to Rachmilewitz index. The rate of total colon observation and colon cleansing level were evaluated. Severity of mucosal inflammation in UC was assessed according to the Mayo endoscopic subscore (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Relapse-free survival was assessed. Acceptability of CCE-2 was assessed using a questionnaire survey. RESULTS: The rate of total colon observation within its battery life was 93.3%. The proportion of "excellent" plus "good" cleansing level was 73.3%. The rate of mucosal healing (MES 0, 1) assessed by CCE-2 was 77.0%. The relapse-free survival rate was significantly higher in MES 0, 1 than in MES 2, 3 (P = 0.0435), and in UCEIS 0-3 than in UCEIS 4-8 (P = 0.0211), whereas there was no significant difference between CAI 0 and CAI 1-4 groups. A questionnaire survey revealed an overall acceptability of CCE. CONCLUSION: CCE-2 is acceptable for assessing the severity of mucosal inflammation in UC patients, especially in clinical remission. Evaluating mucosal healing using CCE-2 was able to predict outcome.

8.
Clin Transl Gastroenterol ; 9(11): 205, 2018 11 14.
Article En | MEDLINE | ID: mdl-30429462

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

9.
Clin Transl Gastroenterol ; 9(10): 192, 2018 10 08.
Article En | MEDLINE | ID: mdl-30310050

A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis.

10.
Clin Transl Gastroenterol ; 9(7): 170, 2018 07 06.
Article En | MEDLINE | ID: mdl-29977035

OBJECTIVES: Adsorptive granulomonocytapheresis (GMA) with the Adacolumn has been introduced as a non-pharmacologic treatment for ulcerative colitis (UC). However, a subset of patients who might respond well to GMA needs to be targeted. This study was conducted at three IBD centers to determine factors affecting the efficacy of GMA in patients with moderately-to-severely active UC. METHODS: From January 2008 to December 2017, a total of 894 active episodes (first attack or relapse) in 593 patients were treated with GMA. Clinical remission was defined as normal stool frequency and no rectal bleeding. Multiple clinical and laboratory parameters at entry were considered for efficacy assessment. RESULTS: Clinical remission was achieved during 422 (47%) of the 894 treatment cases. In the multivariate analysis, predictors for favorable response to GMA were age ≤60 years, UC duration <1 year, Mayo endoscopic subscore 2 (vs. 3), steroid naïve UC, and biologic naïve UC. Clinical remission rate was 70% in patients with four of the five factors, 52% in patients with three factors, 46% in patients with two factors, 39% in patients with one factor, and 18% in patients with none of these factors. Overall, the clinical remission rate was significantly higher in patients with a greater number of the five predictors (P < 0.0001). CONCLUSIONS: GMA appeared to be effective in steroid naïve and biologic naïve patients with short duration of UC. Elderly patients (>60 years) and those with severe endoscopic activity did not respond well to GMA. Additional, well designed, prospective, controlled trials should strengthen our findings.


Colitis, Ulcerative/therapy , Leukapheresis/methods , Adult , Age Factors , Colitis, Ulcerative/pathology , Endoscopy, Gastrointestinal , Female , Granulocytes , Humans , Male , Monocytes , Remission Induction , Retrospective Studies , Severity of Illness Index , Time Factors , Treatment Outcome
11.
Inflamm Bowel Dis ; 23(5): 728-738, 2017 05.
Article En | MEDLINE | ID: mdl-28426455

BACKGROUND: Digoxin, a cardiac glycoside used for the treatment of heart failure, was reported to inhibit the retinoid-related orphan receptor gamma t (RORγt) and attenuate the severity of experimental autoimmune encephalomyelitis and arthritis in mice. However, the effects of digoxin in a mice model of inflammatory bowel disease have not been elucidated. METHODS: Colitis was induced in severe combined immunodeficiency mice by adoptive transfer of CD45RB CD4 T cells. Digoxin or a vehicle was injected into mice with colitis intraperitoneally every other day and changes in body weight were evaluated. After 6 to 8 weeks, the treated mice were killed and evaluated for histological score, T-cell subset, and cytokine messenger RNA (mRNA) expression in the colonic tissue. RESULTS: Wasting disease and histological damage were significantly attenuated in digoxin-treated mice with colitis compared with those in the vehicle-treated mice. In addition, the mRNAs of Th17-related cytokines were downregulated, whereas those of interleukin-10 were upregulated in the colonic mucosa of digoxin-treated mice. However, unexpectedly, the mRNA expression level of tumor necrosis factor alpha did not decrease in the colonic mucosa of digoxin-treated mice with colitis. This observation suggests that digoxin may ameliorate colitis by a tumor necrosis factor alpha-independent pathway. CONCLUSIONS: This study has shown for the first time that treatment with digoxin can ameliorate murine experimental colitis. This finding suggests that the suppression of Th17 using reagents such as digoxin could be effective in treating Crohn's disease refractory to anti-tumor necrosis factor alpha therapy.


Cardiotonic Agents/pharmacology , Colitis/drug therapy , Cytokines/drug effects , Digoxin/pharmacology , Th17 Cells/drug effects , Animals , Colitis/blood , Colitis/etiology , Colon/metabolism , Cytokines/metabolism , Disease Models, Animal , Down-Regulation/drug effects , Female , Intestinal Mucosa/metabolism , Mice , Mice, Inbred BALB C , Mice, SCID , RNA, Messenger/metabolism , Th17 Cells/metabolism , Wasting Syndrome/drug therapy , Wasting Syndrome/etiology
12.
Immunology ; 149(3): 320-328, 2016 Nov.
Article En | MEDLINE | ID: mdl-27421990

Bone-marrow-derived macrophages are divided into two phenotypically and functionally distinct subsets, M1 and M2 macrophages. Recently, it was shown that adoptive transfer of M2-polarized peritoneal macrophages reduced the severity of experimental colitis in mice. However, it is still unclear whether peritoneal macrophages possess the same ability to be polarized to cells with functionally different phenotypes and cytokine production patterns as bone-marrow-derived macrophages. To address this question, we examined the ability of peritoneal macrophages to be polarized to the M1 and M2 phenotypes and determined the specific cytokine profiles of cells with each phenotype. We showed that peritoneal macrophages, as well as bone-marrow-derived macrophages, were differentiated into M1 and M2 phenotypes following stimulation with interferon-γ (IFN-γ) and interleukin-4 (IL-4)/IL-13, respectively. Following in vitro stimulation with lipopolysaccharide, M2-polarized peritoneal macrophages predominantly expressed T helper type 2 (Th2) cytokines and regulatory cytokines, including IL-4, IL-13, transforming growth factor-ß and IL-10, whereas M1-polarized peritoneal macrophages expressed negligible amounts of Th1 and pro-inflammatory cytokines. ELISA showed that M2-polarized peritoneal macrophages produced significantly more IL-10 than M1-polarized peritoneal macrophages. Notably, M2-polarized peritoneal macrophages contributed more to the suppression of T-cell proliferation than did M1-polarized peritoneal macrophages. The mRNA expression of Th2 cytokines, including IL-4 and IL-13, increased in T-cells co-cultured with M2-polarized macrophages. Hence, our findings showed that M2 polarization of peritoneal macrophages induced regulatory cytokine production and suppressed T-cell proliferation in vitro, and that resident peritoneal macrophages could be used as a new adoptive transfer therapy for autoimmune/inflammatory diseases after polarization to the regulatory phenotype ex vivo.


Colitis/immunology , Interleukin-10/metabolism , Macrophages, Peritoneal/immunology , Macrophages/immunology , Th1 Cells/immunology , Th2 Cells/immunology , Transforming Growth Factor beta/metabolism , Animals , Cell Differentiation , Cell Proliferation , Cells, Cultured , Coculture Techniques , Female , Immunosuppression Therapy , Interleukin-10/genetics , Lipopolysaccharides/immunology , Mice , Mice, Inbred C57BL , Phenotype , Transforming Growth Factor beta/genetics
13.
Anal Bioanal Chem ; 406(1): 275-82, 2014 Jan.
Article En | MEDLINE | ID: mdl-24190614

In this study, we introduce the double-barrel carbon probe (DBCP)-a simple, affordable microring electrode-which enables the collection and analysis of single cells independent of cellular positioning. The target cells were punctured by utilizing an electric pulse between the two electrodes in DBCP, and the cellular lysates were collected by manual aspiration using the DBCP. The mRNA in the collected lysate was evaluated quantitatively using real-time PCR. The histograms of single-cell relative gene expression normalized to GAPDH were fit to a theoretical lognormal distribution. In the tissue culture model, we focused on angiogenesis to prove that multiple gene expression analysis was available. Finally, we applied DBCP for the embryonic stem (ES) cell-derived cardiomyocytes to substantiate the capability of the probe to collect cells, even from high-volume samples such as spheroids. This method achieves high sensitivity for mRNA at the single-cell level and is applicable in the analysis of various biological samples independent of cellular positioning.


Human Umbilical Vein Endothelial Cells/chemistry , Myocytes, Cardiac/chemistry , RNA, Messenger/genetics , Single-Cell Analysis/methods , Animals , Biomarkers/metabolism , Cell Differentiation , Cell Line, Tumor , Electricity , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Gene Expression , Genes, Essential , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/genetics , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/metabolism , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Mice , Microelectrodes , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , RNA, Messenger/metabolism , Real-Time Polymerase Chain Reaction
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