Serum anti-DIDO1, anti-CPSF2, and anti-FOXJ2 antibodies as predictive risk markers for acute ischemic stroke.

BACKGROUND: Acute ischemic stroke (AIS) is a serious cause of mortality and disability. AIS is a serious cause of mortality and disability. Early diagnosis of atherosclerosis, which is the major cause of AIS, allows therapeutic intervention before the onset, leading to prevention of AIS. METHODS: Serological identification by cDNA expression cDNA libraries and the protein array method were used for the screening of antigens recognized by serum IgG antibodies in patients with atherosclerosis. Recombinant proteins or synthetic peptides derived from candidate antigens were used as antigens to compare serum IgG levels between healthy donors (HDs) and patients with atherosclerosis-related disease using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay. RESULTS: The first screening using the protein array method identified death-inducer obliterator 1 (DIDO1), forkhead box J2 (FOXJ2), and cleavage and polyadenylation specificity factor (CPSF2) as the target antigens of serum IgG antibodies in patients with AIS. Then, we prepared various antigens including glutathione S-transferase-fused DIDO1 protein as well as peptides of the amino acids 297-311 of DIDO1, 426-440 of FOXJ2, and 607-621 of CPSF2 to examine serum antibody levels. Compared with HDs, a significant increase in antibody levels of the DIDO1 protein and peptide in patients with AIS, transient ischemic attack (TIA), and chronic kidney disease (CKD) but not in those with acute myocardial infarction and diabetes mellitus (DM). Serum anti-FOXJ2 antibody levels were elevated in most patients with atherosclerosis-related diseases, whereas serum anti-CPSF2 antibody levels were associated with AIS, TIA, and DM. Receiver operating characteristic curves showed that serum DIDO1 antibody levels were highly associated with CKD, and correlation analysis revealed that serum anti-FOXJ2 antibody levels were associated with hypertension. A prospective case-control study on ischemic stroke verified that the serum antibody levels of the DIDO1 protein and DIDO1, FOXJ2, and CPSF2 peptides showed significantly higher odds ratios with a risk of AIS in patients with the highest quartile than in those with the lowest quartile, indicating that these antibody markers are useful as risk factors for AIS. CONCLUSIONS: Serum antibody levels of DIDO1, FOXJ2, and CPSF2 are useful in predicting the onset of atherosclerosis-related AIS caused by kidney failure, hypertension, and DM, respectively.

Immunomodulator-associated Epstein-Barr virus-positive mucocutaneous ulcer in a patient with refractory Crohn's disease.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer is a B-cell lymphoproliferative disorder occurring in elderly or iatrogenic immunocompromised patients. We report a 27-year-old male patient with Crohn's disease (CD) who developed immunomodulator-associated lymphoproliferative disorder. The patient was diagnosed with CD at the age of 17 and was treated with maintenance therapy including high-dose infliximab and azathioprine. When he was admitted to our hospital with a diagnosis of intestinal obstruction, his abdominal computed tomography findings showed not only colonic wall thickening and narrowing of the descending colon but also multiple liver tumor lesions. His ileus symptom improved with conservative therapy, and a pathological evaluation of the tissue biopsy specimens from the descending colon and liver lesions indicated a morphological diagnosis of EBV-positive diffuse large B-cell lymphoma. This was a case of iatrogenic immunodeficiency-associated lymphoproliferative disorder due to an immunomodulator. The treatment was initiated with chemotherapy, but he died of disease progression 10 months after the diagnosis of lymphoma. Although cases of lymphoproliferative disorder due to treatment modalities used for CD are rare in Japan, an increase in the risk of lymphoproliferative diseases should be considered in patients with CD treated with immunomodulatory agents.

Comparison of a novel predictor of venous thromboembolic complications in inflammatory bowel disease with current predictors.

BACKGROUND AND AIM: Venous thromboembolism (VTE) is a common complication of inflammatory bowel disease (IBD). The aim of the present study was to identify predictors of VTE in hospitalized patients with IBD. METHODS: Patients with IBD who were hospitalized from February 2015 to March 2016 at the Chiba University Hospital were included. VTE was detected using enhanced computed tomography, and VTE onset within 2 months after admission was assessed. Predictors of VTE onset were investigated with clinical factors during hospitalization. Availability of the Caprini risk assessment model and Padua prediction score at the time of admission was also assessed. RESULTS: Seventy-two patients with IBD were hospitalized, and central venous catheters were placed in 43 of the 72 patients. During the observation period, VTE occurred in six patients (8.3%); however, none died as a result of the condition. Cox proportional hazards regression analysis identified D-dimer values on admission as a risk factor that was highly associated with VTE onset (hazard ratio = 1.590; 95% confidence interval, 1.132-2.233; P = 0.007) and significantly predicted the occurrence of VTE using the receiver operating characteristic curve (P = 0.005, area under the curve = 0.893). However, Caprini risk assessment model and Padua prediction scores were not useful tools for predicting VTE onset in patients with IBD. CONCLUSION: In hospitalized patients with IBD, D-dimer values were highly associated with VTE onset. Therefore, measurement of D-dimer values on admission is critical for the management of thromboembolic complications in patients with IBD.

Clinical characteristics and outcomes of primary sclerosing cholangitis and ulcerative colitis in Japanese patients.

BACKGROUND: In Western countries, most patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). The number of patients with UC in East Asia has increased markedly over the past two decades. However, current clinical features of PSC and of PSC associated with UC (PSC-UC) have not yet been clarified in East Asia, particularly in Japan. We aimed to reveal the clinical courses and associations with UC in Japanese patients with PSC from the mutual viewpoint of PSC and UC. METHODS: We retrospectively retrieved medical records of patients with PSC (69) and UC (1242) who were diagnosed at Chiba University Hospital between June 1991 and August 2017. RESULTS: In the present cohort, 37 patients had PSC-UC; the cumulative risks of PSC in patients with UC and of UC in patients with PSC were 3.0% and 53.6%, respectively. We confirmed similar distinctive results by a Japanese nationwide survey, noting that younger patients with PSC had a notably high possibility of association with UC. From the viewpoint of the UC cohort, the occurrence of right-sided disease was significantly higher in patients with PSC-UC than in those with UC (16.2% vs. 4.2%, P = 0.003). Pancolitis was more commonly observed in PSC-UC, and proctits/left-sided colitis was less commonly found in patients with UC. The number of patients with young-onset PSC-UC may be increasing similar to an increase in patients with UC in Japan. CONCLUSIONS: In our cohort, the comorbidity rate of PSC-UC was higher than that obtained in previous reports. The incidence of PSC-UC and UC may increase in the future in East Asia, particularly in Japan.

Investigation of novel biomarkers for predicting the clinical course in patients with ulcerative colitis.

BACKGROUND: The clinical course of ulcerative colitis (UC) is characterized by repeated episodes of relapse and remission. We hypothesized that biomarkers that help distinguish refractory UC patients who are in remission using strong anti-immunotherapy could contribute in preventing the overuse of corticosteroids for treatment. Here, we clarified novel autoantibodies for UC patients in remission as clinical indicators to distinguish between refractory and non-refractory UC. METHODS: Antigen proteins recognized by serum antibodies of patients with UC in remission were screened using the protein array method. To validate the results, AlphaLISA was used to analyze the serum antibody titers with candidate protein antigens. Serum samples from 101 healthy controls, 121 patients with UC, and 39 patients with Crohn's disease were analyzed. RESULTS: Of 66 candidate protein antigens screened by ProtoArray™, six were selected for this study. The serum titers of anti-poly ADP-ribose glycohydrolase (PARG), anti-transcription elongation factor A protein-like 1, and anti-proline-rich 13 (PRR13) antibodies were significantly higher in patients with UC than in healthy controls. Anti-PARG and anti-PRR13 antibody titers were significantly higher in patients with refractory UC than in patients with non-refractory UC. There were no significant differences in any antibody titer between the active and remission phases. CONCLUSIONS: The serum titers of anti-PARG, anti-transcription elongation factor A protein-like 1, and anti-PRR13 antibodies were elevated in patients with UC. Anti-PARG and anti-PRR13 antibody titers may be novel clinical indicators for detecting refractory UC in patients in remission.

Real-time Endoscopy-Guided Measurement of Rectal Mucosal Admittance Is a Novel and Safe Method for Predicting Ulcerative Colitis Relapse.

Background: There are known associations between inflammatory bowel disease (IBD) and changes in mucosal paracellular permeability. We recently developed a novel catheter that can measure mucosal admittance (MA). Methods: Patients with ulcerative colitis (UC) in clinical remission underwent real-time MA measurement during colonoscopy between June 2014 and July 2015 and were prospectively followed. MA measures were taken from normal-appearing mucosa using the Tissue Conductance Meter (TCM). We examined relationships between mucosal admittance, clinical parameters at the time of MA measurement, and disease relapse during the follow-up period using the Cox proportional hazards model. Results: We measured baseline MA in 54 patients with UC during remission, with no complications. Of these, 23 patients relapsed during the subsequent follow-up period, at a median of 25.8 ± 7.6 months. Rectal MA was the only predictor of disease relapse in multivariate analysis (P = 0.027). The optimal rectal MA cutoff value for relapse was 781.0 (area under the receiver operating characteristic curve, 0.712), and in patients who showed lower than normal cutoff values, there was a significantly higher likelihood of relapse compared with other patients (log-rank test, P < 0.001). Conclusions: High rectal MA measured by TCM is associated with long-term sustained remission. Real-time rectal MA measurement using a novel endoscopy-guided catheter could be a safe and useful means of predicting prognosis for patients with UC in remission.

Long-Term Outcome of Endoscopic Balloon Dilatation for Strictures in Patients with Crohn's Disease.

BACKGROUND/AIMS: Endoscopic balloon dilatation (EBD) is an alternative to surgery for strictures in patients with Crohn's disease (CD). The aim of the present study was to clarify the efficacy and safety of EBD for strictures in patients with CD. METHODS: Twenty-six patients with CD who underwent EBD for strictures from August 2008 to November 2015 were followed up after dilatation. Short-term success was defined as the disappearance of obstructive symptoms after technically adequate dilatation was achieved. The short-term success rate of EBD, safety profile of EBD, and cumulative surgery-free and redilatation-free rates were analyzed. RESULTS: Sixty-five EBDs were performed for CD patients in the follow-up period. The short-term success rate was 100% (26/26), and no complications were encountered during this study. Two (7.7%) patients underwent surgery during the observation period. The cumulative surgery-free rate after the initial EBD was 90.3% at both 2 and 3 years. The cumulative redilatation-free rate after the initial EBD was 52.1% at 2 years and 39.1% at 3 years. CONCLUSION: EBD for strictures secondary to CD provides not only short-term success but also long-term efficacy. Although a high redilatation rate is one of the clinical problems of this procedure, EBD is an effective therapy for avoiding intestinal recession in CD -stricture.

Evaluation of Esophageal Mucosal Integrity in Patients with Gastroesophageal Reflux Disease.

BACKGROUND: Impaired esophageal mucosal integrity plays a role in causing symptoms of gastroesophageal reflux disease (GERD). Recently, the assessment of esophageal baseline impedance (BI) using the multichannel intraluminal impedance-pH (MII-pH) test was suggested as a surrogate technique for the study of esophageal mucosal integrity and was reported to be useful in distinguishing GERD from non-GERD. However, measuring BI requires a 24-h testing period, is complicated, and causes considerable patient discomfort. SUMMARY: Recently, endoscopy-guided catheters that can measure mucosal impedance (MI) and mucosal admittance (MA), which is the inverse of impedance, were developed, and their usefulness in measuring MI and MA for the diagnosis of GERD has been reported. In these studies, esophageal MI values were significantly lower in patients with GERD than in those without GERD. In contrast, esophageal MA was significantly higher in patients with GERD than in those without. Furthermore, we reported that MA is inversely correlated with BI and correlated with acid exposure time. Key Messages: Endoscopy-guided real-time measurement of MI and MA may allow the estimation of mucosal integrity and may be a useful diagnostic tool for patients with GERD in a manner similar to 24-h MII-pH monitoring.

Endoscopy-Guided Evaluation of Duodenal Mucosal Permeability in Functional Dyspepsia.

OBJECTIVES: The pathophysiology of functional dyspepsia (FD) is not fully understood. Impaired duodenal mucosal integrity characterized by increased mucosal permeability and/or low-grade inflammation was reported as potentially important etiologies. We aimed to determine the utility of a recently developed simple catheterization method to measure mucosal admittance (MA), the inverse of mucosal impedance, for evaluation of duodenal mucosal permeability in patients with FD. METHODS: We conducted two prospective studies. In the first study, duodenal MA of 23 subjects was determined by catheterization during upper endoscopy, and transepithelial electrical resistance (TEER) of duodenal biopsy samples in Ussing chambers was measured to assess the correlation between MA and TEER. In the second study, duodenal MA of 21 patients with FD fulfilling the Rome III criteria was compared with that of 23 healthy subjects. RESULTS: The mean MA and TEER values were 367.5±134.7 and 24.5±3.7 Ω cm2, respectively. There was a significant negative correlation between MA and TEER (r=-0.67, P=0.0004, Pearson's correlation coefficient). The mean MA in patients with FD was significantly higher than that in healthy subjects (455.7±137.3 vs. 352.1±66.9, P=0.002, unpaired t-test). No procedure-related complications were present. CONCLUSIONS: We demonstrated the presence of increased duodenal mucosal permeability in patients with FD by MA measurement using a simple catheterization method during upper endoscopy.

The Effect of Ineffective Esophageal Motility on Gastroesophageal Reflux Disease.

BACKGROUND/AIMS: Ineffective esophageal motility (IEM) is the most common gastrointestinal motility disorder. Studies have reported that IEM is related to gastroesophageal reflux disease (GERD). However, the relationship between IEM and GERD remains uncertain. This study aims to clarify this relationship retrospectively. METHODS: We analyzed 195 subjects who underwent high-resolution manometry between January 2011 and September 2016. Of these subjects, 72 had normal esophageal motility (NEM) and 26 had IEM. We investigated differences in the clinical characteristics, severity and duration of GERD symptoms, and comorbid extra-esophageal symptoms of the subjects. Comorbid extra-esophageal symptoms were assessed with the Gastrointestinal Symptom Rating Scale questionnaire. Investigation-defined GERD was diagnosed when erosive esophagitis or abnormal multichannel intraluminal impedance was present. RESULTS: We found no significant difference in the prevalence of IEM between patients with and without GERD (37.5 and 21.1%, respectively; p = 0.174). There were no differences in age, gender, body mass index, presence of hiatal hernia, or duration of GERD between the groups. Compared to patients with NEM, those with IEM were significantly less likely to have comorbid extra-esophageal symptoms (p < 0.05). CONCLUSION: There is no association between IEM and GERD.