Takahide Matsuda

Development of consensus statements for the diagnosis and management of intestinal Behçet's disease using a modified Delphi approach

BackgroundAlthough intestinal Behçets disease has been treated anecdotally with various therapeutic modalities, clinical evidence regarding management of intestinal Behçets disease is lacking. The objective of this study was to develop consensus-based practice guidelines for diagnosis and treatment of intestinal Behçets disease by using a modified Delphi approach.MethodsThree groups of Japanese gastroenterology specialists were involved in the study: moderators, an expert panel, and a professional group. Clinical statements for ratings were extracted from relevant literature, a survey of the professional group, and by discussion among the expert panel. The expert panel rated the clinical statements according to a nine point scale. After the first round of ratings, a panelist meeting was held to discuss areas of disagreement and to clarify areas of uncertainty. The list of clinical statements was revised after the panelist meeting, and a second round of rating was conducted.ResultsThirty-two relevant articles were selected in a literature search, and 35 clinical statements were extracted. An additional 209 clinical statements were developed from the survey and discussion among gastroenterology specialists. In the first and second rounds, 56% and 60% of statements, respectively, received median scores ≥7. The range of scores decreased considerably from the first to the second round.Conclusions5-Aminosalycylic acid, corticosteroids, immunosuppressants, enteral nutrition, total parenteral nutrition, and surgical therapy were considered standard therapy for intestinal Behçets disease. Infliximab, colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapy. Based on a two-round modified Delphi approach, practice guidelines for diagnosis and treatment of intestinal Behçets disease were developed.

Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behcet's disease.

Involvement of excessive Th1 cell functions and heat shock protein expression in the pathogenesis of Behçets disease (BD) has been reported. In this study we have characterized immune responses in intestinal lesions of BD. Peripheral blood lymphocytes (PBL) of BD and healthy controls (HC) and tissue specimens of intestinal Behçets disease (intestinal BD), Crohns disease (CD) and ulcerative colitis (UC) were analysed for mRNA and protein expression by reverse transcriptase‐polymerase chain reaction (PCR) and immunohistochemistry, respectively. PBL of BD patients expressed the Th1‐related chemokine receptor, CCR5 and CXCR3 preferentially compared with those of healthy controls. Intestinal lesions of BD expressed interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α and interleukin (IL)‐12 mRNA, indicating Th1 skewed responses in vivo. mRNA of Txk, a Tec family tyrosine kinase specific to Th1 cells, was expressed in the lesions, suggesting its contribution to the Th1‐dominant responses. In the intestinal samples, CCR5 was detected in all the cases with BD, whereas Th2‐related CCR3 and CCR4 were detected randomly, mainly in the cases with inactive BD and those receiving large amounts of prednisolone, indicating the Th1‐dominant immune responses in the intestinal lesions. As the ligands of CCR5, MIP1α and MIP1β were detected, whereas RANTES was not. Heat shock protein (HSP) 60 was expressed in PBL and intestinal tissues of BD. Th1‐dominant immune responses and HSP60 expression may induce the inflammatory responses and thus be associated with the pathogenesis of intestinal BD.

Efficacy of Rebamipide as Adjunctive Therapy in the Treatment of Recurrent Oral Aphthous Ulcers in Patients with Behçet’s Disease

AbstractBackground: Behçet’s disease (BD) is a recurrent inflammatory disease involving chronic recurrent oral aphthous ulcers (aphthae), uveitis, skin lesions and genital ulcers. We prospectively investigated the efficacy of rebamipide, a gastroprotective drug, against oral aphthous ulcers in BD patients. Methods: In a multicentre, double-blind, placebo-controlled study, 35 patients with BD, having as the main symptom oral aphthosis, were randomised to receive rebamipide 300 mg/day or placebo for 12 to 24 weeks between August 1994 and December 1996. Oral aphthosis must have occurred within 4 weeks prior to enrolment and must have been visible for at least 7 days during that time. Oral aphthae count and pain scores were recorded daily in a diary by the patients themselves. Monthly aphthae count and pain scores were defined as the sum of aphthae count and pain scores for a month, respectively. Investigators rated the global improvement in aphthae count and pain using a 6-point scale. The rate of change in monthly aphthae count and pain scores in the first 3 and last 3 months of treatment were assessed in patients with more severe symptoms whose aphthae count and pain score were >28 at baseline (trial entry). Results: The rate of moderate or marked improvement in aphthae count and pain was 36% (5 of 14 subjects) in the placebo group and 65% (11 of 17 subjects) in the rebamipide group. During months 2 to 6 of treatment, aphthae count tended to increase and reached a peak at month 4 in the placebo group but decreased in the rebamipide group. Pain score decreased to the same extent in both groups for the first 3 months of treatment; however, in the fourth to sixth months of treatment, the pain score tended to increase in the placebo group but decreased in the rebamipide group. In patients with a monthly aphthae pain score >28 at baseline, pain and count scores decreased throughout the 6 months of rebamipide treatment but increased during the last 3 months of treatment in the placebo group (p < 0.01 for the between-group comparisons). Conclusions: Rebamipide is well tolerated and improves the aphthae count and pain score in BD patients. It may therefore be useful in the treatment and prevention of frequently recurrent oral aphthous ulcers (not restricted to BD). Administration of rebamipide is not cumbersome, and it does not cause any discomfort, which corticosteroid ointments for example may do; furthermore, there are no specific adverse drug reactions. Rebamipide is therefore recommended as a long-term treatment for recurrent oral aphthous ulcers.

Involvement of innate immunity in the pathogenesis of intestinal Behçet's disease.

The involvement of excessive T helper 1 (Th1) cell functions in the pathogenesis of Behçets disease (BD) has been reported. We therefore studied Toll‐like receptor (TLR)‐expressing cells, which play important roles in innate immunity in patients with BD. Peripheral blood mononuclear cells (PBMC) of BD and healthy controls, and tissue specimens of intestinal BD and Crohns disease (CD) were analysed for messenger RNA (mRNA) and protein expressions by reverse transcription–polymerase chain reaction and immunostaining respectively. PBMC of BD expressed TLR‐2 and TLR‐4 mRNA almost comparable with healthy controls. Intestinal lesions of BD expressed TLR‐2 and TLR‐4 mRNA consistently. In contrast, TLR‐4 mRNA was expressed preferentially and TLR‐2 mRNA was expressed less frequently in CD lesions. In intestinal samples of BD, TLR‐2 and TLR‐4 mRNA were detected in ileocaecal ulcer lesions, but not in unaffected sites of the same sample, indicating the association of the TLR expression with the disease manifestation of intestinal BD. TLR‐2‐expressing cells which were simultaneously cluster of distribution (CD)68‐positive produced interleukin (IL)‐12 in the lesions, indicating the participation of TLR‐2‐expressing cells in the Th1 skewed responses in vivo. As a possible ligand of TLR‐2, in BD self‐heat shock protein 60 was expressed in peripheral blood lymphocytes and intestinal tissues. Collectively, TLR‐2‐expressing cells as well as TLR‐4‐expressing cells accumulated in the intestinal lesions of BD. IL‐12 produced by TLR‐2‐expressing cells may contribute to the induction of Th1‐dominant immune responses in intestinal BD.

Proteomic surveillance of autoantigens in patients with Behcet's disease by a proteomic approach

To promote an understanding of autoimmunity in BD, we surveyed autoAgs in patients with BD and investigated the prevalence and clinical significance of the identified autoAbs. Specifically, proteins, extracted from peripheral blood mononuclear cells and separated by 2DE, were subjected to WB, using five serum samples from patients with BD. The detected candidate autoAgs were identified by mass spectrometry. As a result, 17 autoantigenic spots were detected by the 2DE‐WB, out of which eight spots were identified. They are enolase‐1, cofilin‐1, vimentin, Rho‐GDI β protein, tubulin‐like protein, and actin‐like proteins. The autoAbs to one of the identified proteins, cofilin‐1, were investigated by WB using a recombinant protein in 30 patients with BD, 35 patients with RA, 32 patients with SLE, and 16 patients with PM/DM. The autoAbs to cofilin‐1 were detected by WB in four (13.3%) of the 30 patients with BD, five (14.3%) of the 35 patients with RA, two (6.3%) of the 32 patients with SLE, and eight (24.2%) of the 33 patients with PM/DM. Our data indicate that the generation of autoAbs to cofilin‐1 may reflect common immunological disorders in BD, RA, and PM/DM. Our data would help understanding of the immunopathology of BD. In addition, the proteomic approach would be a useful way to investigate autoAgs.

Spontaneous Platelet Aggregation in Patients with Behçet’s Disease by Using Laser-Light Scattering Aggregometer

Most of patients with BD had spontaneous small-size aggregation in this system. Moreover, platelet clots (a large-size platelet aggregation) were only detected in patients with BD compared with normal individuals. These date suggest that BD may exhibit spontaneous hyper-coagulation of platelet function.

Efficacy of MK615 for the treatment of patients with liver disorders

AIM To investigate the hepatoprotective effect of MK615, a Japanese apricot extract, in an animal model, and its clinical therapeutic effect. METHODS Wistar rats were administered physiological saline (4 mL/kg) or MK615 solution (4 mL/kg) for 7 d. On the sixth d, acute hepatic injury was induced by administering a single intraperitoneal injection (ip) of D-galactosamine hydrochloride (D-GalN) (600 mg/kg). Plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined, and liver tissues were used for histopathological analysis. Fifty-eight patients with liver disorders [hepatitis C (n = 40), non-alcoholic fatty liver disease (n = 15), and autoimmune liver disease (n = 3)] were orally administered commercially available Misatol ME-containing MK615 (13 g/d) daily for 12 wk. Blood and urine were sampled immediately before and 6 wk, 12 wk, and 16 wk after the start of intake to measure various biochemical parameters. The percentage change in ALT and AST levels after 12 wk from the pre-intake baseline served as a primary endpoint. RESULTS D-GalN effectively induced acute hepatic injury in the rats. At 48 h after the ip injection of D-GalN, the plasma levels of ALT (475.6 ± 191.5 IU/L vs 225.3 ± 194.2 IU/L, P < 0.05) and AST (1253.9 ± 223.4 IU/L vs 621.9 ± 478.2 IU/L, P < 0.05) in the MK615 group were significantly lower than the control group. Scattered single cell necrosis, loss of hepatocytes, and extensive inflammatory cell infiltration were observed in hepatic tissue samples collected from the control group. However, these findings were less pronounced in the group receiving MK615. At the end of the clinical study, serum ALT and AST levels were significantly decreased compared with pre-intake baseline levels from 103.5 ± 58.8 IU/L to 71.8 ± 39.3 IU/L (P < 0.05) and from 93.5 ± 55.6 IU/L to 65.5 ± 34.8 IU/L (P < 0.05), respectively. A reduction of ≥ 30% from the pre-study baseline ALT level was observed in 26 (45%) of the 58 patients, while 25 (43%) patients exhibited similar AST level reductions. The chronic hepatitis C group exhibited significant ALT and AST level reductions from 93.4 ± 51.1 IU/L to 64.6 ± 35.1 IU/L (P < 0.05) and from 94.2 ± 55.5 IU/L to 67.2 ± 35.6 IU/L (P < 0.05), respectively. A reduction of ≥ 30% from the pre-study baseline ALT level was observed in 20 (50%) of the 40 patients. ALT levels in both the combined ursodeoxycholic acid (UDCA) treatment and the UDCA uncombined groups were significantly lower after Misatol ME administration. MK615 protected hepatocytes from D-GalN-induced cytotoxicity in rats. Misatol ME decreased elevated ALT and AST levels in patients with liver disorders. CONCLUSION These results suggest that MK615 and Misatol ME are promising hepatoprotective agents for patients with liver disorders.

Hepatitis viral infection in Behçet's disease

To elucidate the role of hepatitis viruses in the pathogenesis of Behçets disease (BD), we measured hepatitis viral markers (anti-hepatitis A (anti-HA), HBsAg, anti-HBs, anti-HBc) and viral nucleic acids (hepatitis B virus (HBV)-DNA, hepatitis C virus (HCV)-RNA, GB virus C (GBV-C)-RNA, TT virus (TTV)-DNA) in the sera of 68 BD patients along with 76 blood donors matched for age and sex. Positivity of anti-HA in patients with BD (36.8%) was lower than that in blood donors (68.0%). Both anti-HCV and HCV-RNA were detected in only one (1.5%) patient with BD and in none of the blood donors. The prevalence ratios of HBsAg, anti-HBs, anti-HBc in both groups were similar (2.9:0, 16.2:15.8 and 17.7:19.7%, respectively). However, serum HBV-DNA was detected more frequently in BD patients (8/68; 11.8%) than in blood donors (2/76; 2.6%) (P<0.05). The prevalence of GBV-C-RNA was also higher in patients with BD (4/68; 5.9%) compared with blood donors (0%). However, characteristics and clinical features are similar between GBV-C-RNA-positive and -negative groups. With respect to the prevalence of TTV-DNA, there was no significant difference between BD patients (23.5%) and blood donors (30.3%). Our study indicates that HBV and GBV-C infection might be related to BD, although the role of these viruses remains to be investigated.

Factors predicting the cause and prognosis of central line-associated bloodstream infections

The increased use of indwelling catheters has led to an increased number of deaths due to central line-associated bloodstream infection (CLABSI). Improving CLABSI outcomes requires the identification of clinical characteristics affecting drug selection and factors associated with poor prognosis. The medical records of inpatients admitted to St. Marianna University School of Medicine between April 1, 2010 and March 31, 2013 were evaluated for the results of catheter tip cultures. The clinical characteristics of these cases and the characteristics of the pathogens involved were investigated to identify prognostic factors. Of the 1629 catheter cultures investigated, 183 were CLABSIs. Among them, 105 were caused by gram-positive bacteria, 43 by gram-negative bacteria, and 35 by fungi. Gram-negative CLABSIs were more common in cases with prior colonization by gram-negative bacteria and post-surgical cases. Fungal CLASBIs were more common in the cases with prior colonization by fungi, high-calorie infusion enforcement, broad-spectrum antibiotic treatment, and post-surgical cases. Death was significantly more likely in cases with findings of inflammation at the catheter insertion site and in those with abnormal body temperature, tachycardia, or abnormal white blood cell count. Thus, when treating CLABSI in post-surgical cases and in cases with prior colonization by gram-negative bacteria, therapy should include anti-pseudomonal agents. Considering the factors predicting poor prognostic identified in this study, clinicians must check the vital signs and catheter insertion site in patients with indwelling catheters.

Behçet’s Disease with Vascular Involvement: The Contribution of Anticardiolipin Antibodies and Thrombomodulin

Patients were included by clinical records between 1998 and 2002 at our division. All patients met with international criteria of BD. Lupus anticoagulant (LA) assay was performed by Russell’s viper venom time (dRVVT) and dilute APTT (dAPTT). Anticardiolipin antibodies (aCl-beta2GP I) were assayed with specific EIA for beta2-glycoprotein I (Yamasa kit, Tokyo, Japan). “Vascular involvement” included deep venous thrombosis, subcutaneous thrombophlebitis, arteritis, and various types of venous occlusion (Table 1).