Pretreatment serum monocyte chemoattractant protein-1 as a predictor of long-term outcome by ustekinumab in patients with Crohn's disease.

BACKGROUND AND AIMS: Ustekinumab has been proven to be effective for treatment of patients with Crohn's disease; however, 30-40% of patients have been reported to lose clinical response within 2 years. We aimed to evaluate the efficacy of ustekinumab and identify predictors of short-term and long-term efficacy in Crohn's disease. METHODS: Patients with Crohn's disease receiving their first ustekinumab infusion in our hospital between June 2017 and September 2020 were prospectively enrolled. Concentrations of serum cytokines and chemokines were measured using a multiplex bead array assay. RESULTS: Fifty-nine Crohn's disease patients were enrolled in this study. Among 34 clinically active patients, 38.2% achieved a clinical response at week 8. None of the assayed factors were associated with short-term clinical response. Cumulative persistence rates of ustekinumab were 77.6% at 1 year and 58.9% at 2 years. Univariate Cox regression analysis revealed that Harvey-Bradshaw Index scores at baseline, concomitant immunomodulator treatment, and concentrations of interferon gamma-induced protein-10, monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-1RA, IL-4, IL-6, and IL-8 were significantly associated with loss of efficacy. Multivariate Cox regression analysis found that biologic naïve status (hazard ratio [HR]: 0.1191, 95% confidence interval [CI]: 0.02458-0.5774) and MCP-1 concentrations (HR: 1.038, 95% CI: 1.015-1.062) were significantly and associated with loss of sustained efficacy for ustekinumab treatment. CONCLUSIONS: Our findings suggest that pretreatment serum MCP-1 analysis, combined with a history of biologic use, could be a novel biomarker for predicting the long-term efficacy of ustekinumab in patients with Crohn's disease.

Neutrophil-to-lymphocyte ratio may predict clinical relapse in ulcerative colitis patients with mucosal healing.

Endoscopic mucosal healing (MH) is an important treatment goal for patients with ulcerative colitis (UC). The neutrophil-to-lymphocyte ratio (NLR) reflects systemic inflammation and has been reported to be a useful predictive marker for UC. This study aimed to evaluate the clinical utility of the NLR for predicting clinical relapse in UC patients with MH. We retrospectively enrolled patients with UC who underwent colonoscopy at the Osaka City University Hospital between January 2010 and December 2010, whose Mayo Endoscopic Subscore was 0 or 1. The correlation between the incidence of relapse and demographic factors, including the NLR, was analyzed. We included 129 patients in the present study. The median NLR at the time of endoscopy was 1.98, and differences in the high NLR group and the low NLR group were compared. During a median follow-up period of 46.4 months, 58 patients (45.0%) experienced relapse. The cumulative relapse-free rate was significantly higher in the low NLR group than in the high NLR group (P = 0.03, log-rank test). Multivariate analysis identified high NLR as an independent prognostic factor for clinical relapse (hazard ratio, 1.74; 95% confidence interval, 1.02-2.98; P = 0.04). NLR is a novel and useful predictor of clinical relapse in UC patients with MH, and it can potentially be a strong indicator to determine the appropriate treatment strategy and decision-making in clinical practice.

Effect of the Coronavirus Disease 2019 Lockdown on Lifestyle Factors in Japanese Patients with Inflammatory Bowel Disease.

Objective To examine the effect of the coronavirus disease 2019 (COVID-19) lockdown on lifestyle factors and psychological stress in patients with inflammatory bowel disease (IBD). Methods A retrospective study was conducted on patients with IBD in Japan 2 months after the initiation of the first state of emergency (June 16 to August 21, 2020). A self-reported questionnaire was used to collect data, and lifestyle factors and psychological stress levels before and after the state of emergency were compared. Patients Patients with IBD who were followed up regularly at Osaka City University Hospital from June 16 to August 21, 2020, were included and were classified into elderly (≥65 years old) and non-elderly groups (<65 years old). Results The study sample comprised 451 responders (241, ulcerative colitis; 210, Crohn's disease; 0, COVID-19). The sleep duration increased, whereas the exercise, working, and walking durations decreased during the COVID-19 lockdown. The proportion of patients with psychological stress due to COVID-19, those with an inability to exercise, and those staying indoors increased significantly during COVID-19 lockdown. Lifestyle factors changed more markedly in non-elderly patients, those who were more stressed due to COVID-19, those with the inability to exercise, and those staying indoors during COVID-19 lockdown. Among elderly patients, no significant changes were identified in stress-causing factors. Conclusion The COVID-19 lockdown affected lifestyle factors and psychological stress in patients with IBD, particularly non-elderly patients. These findings may be helpful in suggesting favorable lifestyle changes for patients with IBD.

Lustrous White Erosions Surrounded by an Erythematous Mucosa: A Novel Endoscopic Finding of Gastric Lesions in Patients with Wilson Disease.

Wilson disease is an inherited copper metabolism disorder. We herein report a novel endoscopic finding in three men with Wilson disease. These patients underwent upper endoscopy due to gastrointestinal symptoms or during follow-up. In each case, endoscopy revealed lustrous white erosions surrounded by an erythematous mucosa in the greater curvature of the gastric body. A biopsy of the lesions showed orcein-positive tissue, indicating copper deposition, in the interstitial stroma and fundic glands of the mucosa. All patients had been receiving treatment with zinc acetate. These endoscopic findings might have been related to the cytotoxicity of the accumulated copper and zinc acetate.

Impact of the Lockdown Due to the COVID-19 Pandemic on Patients With Inflammatory Bowel Disease.

Background: The government of Japan declared a state of emergency on April 16, 2020, owing to the coronavirus disease 2019 (COVID-19) pandemic. The subsequent lockdown altered lifestyles and worsened mental illnesses. Inflammatory bowel disease (IBD) is an intestinal disorder that is affected by environmental factors. Therefore, we aimed to assess the effects of COVID-19 and the state of emergency on the lifestyle and disease activity of patients with IBD. Methods: We conducted a questionnaire survey on patients with IBD from June 16 to August 21, 2020 during their regular follow-up at our hospital, 2 months after the state of emergency was declared. Results: Overall, 241 patients with ulcerative colitis (UC) and 210 with Crohn's disease (CD) completed the survey, of which 82 (34%) and 97 (46%) patients, respectively, reported disease exacerbation within 2 months after the lockdown. Multivariate logistic regression analysis identified age at enrollment (odds ratio, OR 0.98, 95% CI 0.96-0.99; P < 0.05), sleep hours (OR, 0.74; 95% CI, 0.57-0.97; P < 0.05), and increased stress due to the COVID-19 pandemic (OR, 6.06; 95% CI, 1.79-20.50; P < 0.01) as independent factors associated with UC exacerbation. Patients with exacerbated CD were younger at CD onset and had higher patient-reported outcome 2 scores before the state of emergency than patients with non-exacerbated CD. On multivariate analysis, age (OR, 0.97; 95% CI, 0.95-0.99; P < 0.01) and active disease before the state of emergency (OR, 2.20; 95% CI, 1.23-3.95; P < 0.01) were independently associated with CD exacerbation. Conclusions: Improving sleep quality and preventing psychological stress may be crucial in IBD management during a pandemic, especially in young patients.

The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients.

Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)-25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)-24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2-25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2-25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.

Endoscopic findings of gastric lesions in patients with eosinophilic gastrointestinal disorders.

Background and study aims Eosinophilic gastrointestinal disorders are classified into eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis according to the site of eosinophilic infiltration. Although well established in eosinophilic esophagitis, endoscopic findings in eosinophilic gastritis and eosinophilic gastroenteritis with regard to gastric lesions have not been clearly described. The aim of this study was to identify endoscopic findings of gastric lesions associated with eosinophilic gastrointestinal disorders. Patients and methods Out of 278 patients with eosinophilic gastrointestinal disorders, 18 had eosinophilic gastritis or eosinophilic gastroenteritis confirmed by biopsy; their endoscopic images were analyzed retrospectively. The association between endoscopic findings and number of eosinophils in the gastric mucosa was investigated. Results Erythema was most frequently observed (72 %), followed by ulcers (39 %), discoloration (33 %), erosions (28 %), nodularity (28 %), and polyps (28 %). There were several unique endoscopic findings such as submucosal tumor-like deep large ulcers in three patients, antral Penthorum -like appearances (small nodules radially lined toward the pyloric ring) in three patients, "muskmelon-like appearances" (discolored mucosa-composed mesh pattern) in three patients, multiple white granular elevations in two patients, cracks (appearance of furrows similar to those in eosinophilic esophagitis) in five patients, and antral rings in one patient. No significant association was observed between endoscopic findings and number of gastric eosinophils. Conclusions Several unique endoscopic findings of gastric lesions were observed in patients with eosinophilic gastritis or eosinophilic gastroenteritis. Submucosal tumor-like ulcers, antral Penthorum -like appearances, muskmelon-like appearances, and cracks might be associated with eosinophilic gastrointestinal disorders.

Novel prognostic biomarkers of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis: Neutrophil-to-lymphocyte ratio.

OBJECTIVES: Pouchitis is a major complication after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). Although there have been many investigations of the neutrophil-to-lymphocyte ratio (NLR) in various diseases, its role in predicting the development of pouchitis remains unclear. We aimed to evaluate the clinical utility of the NLR for predicting the development of pouchitis after IPAA in UC patients. MATERIALS AND METHODS: UC patients who underwent IPAA at Osaka City University Hospital between May 2006 and March 2019 were included. The incidence of pouchitis was estimated using the Kaplan-Meier method. Potential preoperative, intraoperative, and postoperative predictors for pouchitis, including various demographic and clinical variables, were analyzed. The combined impact of the NLR and other known prognostic factors were investigated using Cox proportional hazard regression with inverse probability of treatment weighting (IPTW). RESULTS: Forty-nine patients with UC who underwent IPAA were included. The median follow-up period was 18.3 months (interquartile range: 10.7-47.2 months). Eighteen patients (36.7%) developed pouchitis. The incidence of pouchitis was 19.2%, 32.6%, and 45.9% at 1, 2, and 5 years, respectively. NLR was significantly associated with the development of pouchitis in the univariate Cox regression analysis (hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.01-1.28; P = 0.03). The NLR cutoff value of 2.15 was predictive of the development of pouchitis according to receiver operating characteristic analysis (specificity: 67.7%, sensitivity: 72.2%). The incidence of pouchitis was significantly lower in the low NLR group than that in the high NLR group (P = 0.01, log-rank test). Cox regression analyses using IPTW also identified NLR as a prognostic factor for the development of pouchitis by statistically adjusting for background factors (HR, 3.60; 95% CI, 1.31-9.89; P = 0.01). CONCLUSIONS: NLR may be a novel and useful indicator for predicting the development of pouchitis after IPAA in UC and should be introduced in clinical practice.

Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene.

Loss-of-function mutations in the solute carrier organic anion transporter family, member 2a1 gene (SLCO2A1), which encodes a prostaglandin (PG) transporter, have been identified as causes of chronic nonspecific multiple ulcers in the small intestine; however, the underlying mechanisms have not been revealed. We, therefore, evaluated the effects of systemic knockout of Slco2a1 (Slco2a1-/-) and conditional knockout in intestinal epithelial cells (Slco2a1ΔIEC) and macrophages (Slco2a1ΔMP) in mice with dextran sodium sulphate (DSS)-induced acute colitis. Slco2a-/- mice were more susceptible to DSS-induced colitis than wild-type (WT) mice, but did not spontaneously develop enteritis or colitis. The nucleotide-binding domain, leucine-rich repeats containing family, pyrin domain-containing-3 (NLRP3) inflammasome was more strongly upregulated in colon tissues of Slco2a-/- mice administered DSS and in macrophages isolated from Slco2a1-/- mice than in the WT counterparts. Slco2a1ΔMP, but not Slco2a1ΔIEC mice, were more susceptible to DSS-induced colitis than WT mice, partly phenocopying Slco2a-/- mice. Concentrations of PGE2 in colon tissues and macrophages from Slco2a1-/- mice were significantly higher than those of WT mice. Blockade of inflammasome activation suppressed the exacerbation of colitis. These results indicated that Slco2a1-deficiency increases the PGE2 concentration, resulting in NLRP3 inflammasome activation in macrophages, thus exacerbating intestinal inflammation.

Azathioprine Is Useful for Maintaining Long-term Remission Induced by Tacrolimus for the Treatment of Ulcerative Colitis: An Inverse Probability of a Treatment Weighing Analysis.

Objective The need for and efficacy of immunomodulators for maintaining remission after tacrolimus therapy have not been sufficiently defined. This study evaluated the efficacy of immunomodulators for maintaining remission in patients with ulcerative colitis after tacrolimus therapy. Methods Patients with active ulcerative colitis who started oral tacrolimus between January 2009 and September 2017 and were responsive were retrospectively evaluated. Long-term outcomes were compared using Cox proportional hazard regression with inverse probability of treatment weighting. Results Among the 63 patients in the study, 45 received immunomodulators. During the follow-up, 30 patients (47.6%) experienced a relapse. The relapse-free survival rate was significantly worse in the group that did not receive immunomodulators than in those that did (p=0.01, log-rank test); the 2-year relapse-free rates were 22.5% and 63.6% in the non-immunomodulator and immunomodulator groups, respectively. A multivariate analysis showed immunomodulator treatment to be an independent protective factor for clinical relapse (adjusted hazard ratio: 0.35, 95% confidence interval: 0.16-0.78, p=0.01). A Cox regression analysis using inverse probability of treatment weighting also showed that immunomodulator maintenance therapy was correlated with a longer relapse-free survival (hazard ratio: 0.31, 95% confidence interval: 0.15-0.64, p<0.01), A similar response was also observed in non-steroid-dependent patients (hazard ratio: 0.36, 95% confidence interval: 0.14-0.99, p=0.047). No serious adverse events occurred due to tacrolimus or immunomodulator, and immunomodulator use did not increase the incidence of adverse events caused by tacrolimus. Conclusion Our data suggest that the use of immunomodulators to maintain remission after tacrolimus therapy is beneficial for patients with ulcerative colitis.

Pretreatment neutrophil-to-lymphocyte ratio predicts clinical relapse of ulcerative colitis after tacrolimus induction.

OBJECTIVES: Although tacrolimus is useful as an induction therapy in patients with ulcerative colitis (UC), information regarding the long-term outcome after tacrolimus therapy is insufficient. The aim of this study was to evaluate the clinical significance of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor in patients with UC receiving tacrolimus, to aid treatment selection. MATERIALS AND METHODS: Patients with moderate-to-severe active UC who received oral tacrolimus induction therapy and subsequent immunomodulatory maintenance therapy at our hospital between 2009 and 2017 and who showed clinical response at week 12, were retrospectively enrolled. Cox regression analysis was conducted to study the prognostic role of the pretreatment NLR. The combined impact of the NLR and other known prognostic factors was investigated with multivariate regression. RESULTS: Among 45 patients included in this study, 21 patients experienced relapse during a median follow-up period of 16.6 months. Multivariate Cox regression analysis identified the pretreatment NLR (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.72-0.94, P < 0.01) and the use of immunomodulators at the start of tacrolimus treatment (HR: 0.18, 95% CI: 0.05-0.66, P = 0.01) as independent predictors of clinical relapse. CONCLUSIONS: The pretreatment NLR is an independent prognostic factor in patients with UC treated with tacrolimus.

Involvement of gliadin, a component of wheat gluten, in increased intestinal permeability leading to non-steroidal anti-inflammatory drug-induced small-intestinal damage.

Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1ß in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism.

Sepsis Markers Soluble IL-2 Receptor and Soluble CD14 Subtype as Potential Biomarkers for Complete Mucosal Healing in Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Novel noninvasive biomarkers with high diagnostic accuracy are required to assess mucosal healing, which is associated with sustained clinical remission, in inflammatory bowel disease. This study aimed to explore sepsis markers as potential biomarkers for mucosal healing. METHODS: Patients with ulcerative colitis [UC] or Crohn's disease [CD], who underwent blood tests for C-reactive protein [CRP], serum procalcitonin [PCT], soluble interleukin-2 receptor [sIL-2R], and plasma soluble CD14 subtype [sCD14-ST] within 2 weeks of endoscopy, were retrospectively recruited; and we assessed the relationship between marker levels and clinical features. Complete mucosal healing [cMH] was defined as a Mayo endoscopic subscore [MES] of 0 for UC and a simple endoscopic score for Crohn's disease [SES-CD] of 0 for CD. RESULTS: In all, 68 UC patients and 33 CD patients were included in this study. In patients with UC, the sIL-2R level was significantly higher in patients without cMH than in those with cMH. The sIL-2R level had the highest diagnostic value for identifying cMH in UC. In patients with CD, CRP and sCD14-ST levels were significantly higher in patients without cMH than in those with cMH, and both CRP and sCD14-ST had good diagnostic values for identifying cMH. The sCD14-ST level had a high diagnostic value for identifying cMH even among CD patients with complete clinical remission, defined as a Harvey-Bradshaw index of 0. CONCLUSIONS: The sIL-2R and sCD14-ST levels in patients with UC and CD, respectively, can be useful surrogate markers for identifying mucosal healing in inflammatory bowel disease.

NLRP3 inflammasome has a protective effect against oxazolone-induced colitis: a possible role in ulcerative colitis.

The inflammasomes induce maturation of pro-interleukin-1ß (IL-1ß) and pro-IL-18. We investigated roles of the NLRP3 inflammasome in the pathogenesis of ulcerative colitis (UC). After induction of oxazolone-induced colitis, a mouse UC model, colonic tissues were assayed for inflammatory mediators. Histological studies were performed on inflamed colonic tissue from mice and UC patients. Histological severity of murine colitis peaked on day 1, accompanied by an increase in the expression of Th2 cytokines including IL-4 and IL-13. Oxazolone treatment stimulated maturation of pro-caspase-1 and pro-IL-1ß, while it reduced IL-18 expression. Either exogenous IL-1ß or IL-18 ameliorated the colitis with or without reduction in Th2 cytokine expression, respectively. Induction of colitis decreased MUC2 expression, which was reversed by administration of IL-18, but not IL-1ß. Compared to wild-type mice, NLRP3-/- mice exhibited higher sensitivity to oxazolone treatment with enhancement of Th2 cytokine expression and reduction of mature IL-1ß and IL-18 production; this phenotype was rescued by exogenous IL-1ß or IL-18. Immunofluorescent studies revealed positive correlation of NLRP3 expression with disease severity in UC patients, and localization of the inflammasome-associated molecules in macrophages. The NLRP3 inflammasome-derived IL-1ß and IL-18 may play a protective role against UC through different mechanisms.

Colchicine prevents NSAID-induced small intestinal injury by inhibiting activation of the NLRP3 inflammasome.

The inflammasome is a large, multiprotein complex that consists of a nucleotide-binding oligomerization domain-like receptor (NLR), an apoptosis-associated speck-like protein containing a caspase recruitment domain, and pro-caspase-1. Activation of the inflammasome results in cleavage of pro-caspase-1 into cleaved caspase-1, which promotes the processing of pro-interleukin (IL)-1ß into mature IL-1ß. We investigated the effects of colchicine on non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal injury and activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. Colchicine treatment inhibited indomethacin-induced small intestinal injury by 86% (1 mg/kg) and 94% (3 mg/kg) as indicated by the lesion index 24 h after indomethacin administration. Colchicine inhibited the protein expression of cleaved caspase-1 and mature IL-1ß, without affecting the mRNA expression of NLRP3 and IL-1ß. Although treatment with recombinant IL-1ß (0.1 µg/kg) did not change the severity of small intestinal damage, the preventive effects of colchicine were abolished by supplementation with the same dose of recombinant IL-1ß. Indomethacin-induced small intestinal damage was reduced by 77%, as determined by the lesion index in NLRP3(-/-) mice, and colchicine treatment failed to inhibit small intestinal damage in NLRP3(-/-) mice. These results demonstrate that colchicine prevents NSAID-induced small intestinal injury by inhibiting activation of the NLRP3 inflammasome.