Publications by authors named "Yoshiaki Ishigatsubo"

340 Publications

Changes in the proportion of clinical clusters contribute to the phenotypic evolution of Behçet's disease in Japan.

Arthritis Res Ther 2021 02 1;23(1):49. Epub 2021 Feb 1.

Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Background: We hypothesized that Behçet's disease (BD) consists of several clinical subtypes with different severity, resulting in heterogeneity of the disease. Here, we conducted a study to identify clinical clusters of BD.

Methods: A total of 657 patients registered in the Yokohama City University (YCU) regional BD registry between 1990 and 2018, as well as 6754 patients who were initially registered in the Japanese Ministry of Health, Labour and Welfare (MHLW) database between 2003 and 2014, were investigated. The YCU registry data regarding the clinical manifestations of BD, human leukocyte antigen (HLA) status, treatments, and hospitalizations were analyzed first, followed by similar analyses of the MHLW for validation. A hierarchical cluster analysis was independently performed in both patient groups.

Results: A hierarchical cluster analysis determined five independent clinical clusters in the YCU cohort. Individual counterparts of the YCU clusters were confirmed in the MHLW registry. Recent phenotypical evolutions of BD in Japan, such as increased gastrointestinal (GI) involvement, reduced complete type according to the Japan Criteria, and reduced HLA-B51 positivity were associated with chronologically changing proportions of the clinical clusters.

Conclusions: In this study, we identified independent clinical clusters among BD patients in Japan and found that the proportion of each cluster varied over time. We propose five independent clusters namely "mucocutaneous", "mucocutaneous with arthritis", "neuro", "GI", and "eye."
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http://dx.doi.org/10.1186/s13075-020-02406-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851921PMC
February 2021

Recommendations for the Management of Neuro-Behçet's Disease by the Japanese National Research Committee for Behçet's Disease.

Intern Med 2020 Oct 30;59(19):2359-2367. Epub 2020 Jun 30.

Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Japan.

Objective Brain parenchymal involvement in Behçet's disease (BD) (neuro-Behçet's disease, NB) can be classified into acute type (ANB) and chronic progressive type (CPNB) based on differences in the clinical course and responses to corticosteroid treatment. The present study developed evidence-based recommendations for the management of NB.Methods The task force of the research subcommittee consisted of seven board-certified rheumatologists (one was also a board-certified neurologist) and three board-certified neurologists. First, several clinical questions (CQs) were established. A systematic literature search was performed by The Japan Medical Library Association in order to develop recommendations. The final recommendations for each CQ developed from three blind Delphi rounds, for which the rate of agreement scores [range 1 (strongly disagree)-5(strongly agree)] was determined through voting by the task force.Results A flow chart of the algorithm was established for the management of ANB and CPNB. Thirteen recommendations were developed for NB (general 1, ANB 7, CPNB 5). The strength of each recommendation was established based on the evidence level as well as the rate of agreement.Conclusion The recommendations generated in this study are based on the results of uncontrolled evidence from open trials, retrospective cohort studies and expert opinions, due to the lack of randomized clinical trials. Nevertheless, these recommendations can be used for international studies, although verification by further properly designed controlled clinical trials is required.
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http://dx.doi.org/10.2169/internalmedicine.4705-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644487PMC
October 2020

Trial of Apremilast for Oral Ulcers in Behçet's Syndrome.

N Engl J Med 2019 11;381(20):1918-1928

From Istanbul University-Cerrahpaşa, Cerrahpaşa Medical School and Behçet's Disease Research Center, Istanbul, Turkey (G.H., M.M.); Hospital Saint-Louis, University Paris Diderot, Paris (A.M.); Yokohama City University Graduate School of Medicine, Yokohama (Y.I.), and Nippon Medical School, Graduate School of Medicine, Tokyo (M.T.) - both in Japan; Seoul National University and Seoul National University Hospital (Y.-W.S.) and Yonsei University College of Medicine and Severance Hospital (D.K.), Seoul, South Korea; Celgene, Summit, NJ (S.C., S.M., M.P., M.C.); and New York University School of Medicine, New York (Y.Y.).

Background: The small-molecule phosphodiesterase 4 inhibitor apremilast modulates cytokines that are up-regulated in Behçet's syndrome. In a phase 2 trial involving patients with Behçet's syndrome, apremilast reduced the incidence and severity of oral ulcers. Data on the efficacy and safety of apremilast in patients with Behçet's syndrome who had active oral ulcers and had not previously received biologic agents are limited.

Methods: In a phase 3 trial, we randomly assigned, in a 1:1 ratio, patients who had Behçet's syndrome with active oral ulcers but no major organ involvement to receive either apremilast at a dose of 30 mg or placebo, administered orally, twice daily for 12 weeks, followed by a 52-week extension phase. The primary end point was the area under the curve (AUC) for the total number of oral ulcers during the 12-week placebo-controlled period (with lower values indicating fewer ulcers). There were 13 secondary end points, including complete response of oral ulcers, change from baseline in pain associated with oral ulcers, disease activity, and change from baseline in the Behçet's Disease Quality of Life score (range, 0 to 30, with higher scores indicating greater impairment in quality of life). Safety was also assessed.

Results: A total of 207 patients underwent randomization (104 patients to the apremilast group and 103 to the placebo group). The AUC for the number of oral ulcers was 129.5 for apremilast, as compared with 222.1 for placebo (least-squares mean difference, -92.6; 95% confidence interval [CI], -130.6 to -54.6; P<0.001). The change from baseline in the Behçet's Disease Quality of Life score was -4.3 points in the apremilast group, as compared with -1.2 points in the placebo group (least-squares mean difference, -3.1 points; 95% CI, -4.9 to -1.3). Adverse events with apremilast included diarrhea, nausea, and headache.

Conclusions: In patients with oral ulcers associated with Behçet's syndrome, apremilast resulted in a greater reduction in the number of oral ulcers than placebo but was associated with adverse events, including diarrhea, nausea, and headache. (Funded by Celgene; ClinicalTrials.gov number, NCT02307513.).
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http://dx.doi.org/10.1056/NEJMoa1816594DOI Listing
November 2019

Clinical features of early-stage possible Behçet's disease patients with a variant-type major organ involvement in Japan.

Mod Rheumatol 2019 Jul 28;29(4):640-646. Epub 2018 Nov 28.

a Department of Ophthalmology and Visual Science , Yokohama City University Graduate School of Medicine , Yokohama , Japan.

Clinical data of patients with entro-, vasculo-, and neuro-variant possible Behçet's disease (BD) based on Japanese criteria has not yet comprehensively reported. This ongoing nation-wide registration has been carried out by the Japanese Ministry of Health, Labour and Welfare. The Ministry asked physicians who diagnosed a patient with confirmed or possible BD to register the patient data by filling out a registration form. The Ministry provided us with the dataset after unlinkable anonymization. We analyzed 2003-2014 database generated from the early stage new cases. Among the 7950 analyzable cases, 694 (8.7%) had variant-type possible BD without satisfying complete/incomplete criteria. Of the 694 patients, 479, 46, and 169 had entero-, vasculo-, and neuro-variant possible BD, respectively. Out of these 694 patients, 35 (5.0%) and 154 (22.2%) satisfied the International Study Group criteria and the International Criteria of BD, respectively. Entero-variant possible patients rarely (1.8%) had ocular lesions. Patients with vasculo-variant possible BD were featured by low genital ulceration risk (6.8%) and frequent positive HLA-B51 (60.0%). Neuro-variant possible BD was featured by high median age at registration (48 year). Vasculo- (69.6%) and neuro-variant (68.6%) BD patients showed clear male dominance. Epididymitis was very rare among variant-type possible BD men. We analyzed 694 early-stage variant-type possible BD cases. We believe the data from our study will contribute to further international discussion regarding BD diagnostic criteria and clarification of the clinical presentations of the Japanese variant-type possible BD patients.
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http://dx.doi.org/10.1080/14397595.2018.1494501DOI Listing
July 2019

The ocular involvement did not accompany with the genital ulcer or the gastrointestinal symptoms at the early stage of Behçet's disease.

Mod Rheumatol 2019 Mar 15;29(2):357-362. Epub 2018 May 15.

a Department of Ophthalmology and Visual Science , Yokohama City University Graduate School of Medicine , Yokohama , Japan.

Objectives: This study aimed to identify patients with high-probability of ocular involvement of Behçet's disease (BD).

Methods: The Japanese Ministry of Health, Labour and Welfare provided dataset of ongoing nationwide BD registration project. A patient who had confirmed BD and who was suspected to have BD was registered. We mainly analyzed newly registered patients who had the data for all demographic and diagnostic parameters regardless of fulfilment of any diagnostic criteria.

Results: Among 3213 patients with confirmed or possible BD, 1382 (43.0%) were men and 1831 (57.0%) were women with a median age of 38 years (interquartile range (IQR) 30-49 years). The median duration between onset and registration was 0 year (IQR 0-3). A binomial multivariable logistic regression analysis revealed that being female (odds ratio (OR) 0.63, 95% confidence interval (CI) 0.53-0.75, p < .001), duration since onset (OR 1.33 per 10 years, 95% CI 1.18-1.51, p < .001), genital ulceration (OR 0.28, 95% CI 0.23-0.34, p < .001), and gastrointestinal symptoms (OR 0.36, 95% CI 0.30-0.44, p < .001) were related to the ocular lesion. Analyses based on data of 2800 patients who satisfied International criteria of BD, age-, sex-, duration-based subgroup analyses, analyses targeting iridocyclitis and retino-uveitis, and analysis including patients with missing data confirmed that the four factors were associated with the probability of eye involvement.

Conclusion: The ocular involvement did not accompany with genital ulcer or gastrointestinal symptoms at the early stage of BD.
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http://dx.doi.org/10.1080/14397595.2018.1457424DOI Listing
March 2019

Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus.

Mod Rheumatol 2018 Nov 23;28(6):993-1003. Epub 2018 Feb 23.

a Department of Stem Cell and Immune Regulation , Yokohama City University Graduate School of Medicine , Yokohama , Japan.

Objectives: TRIM21 is an E3 ubiquitin ligase for interferon regulatory factors (IRFs) that are involved in innate and acquired immunity. Here, we evaluated the role of TRIM21 in the interferon (IFN) signature of systemic lupus erythematosus (SLE).

Methods: Twenty SLE patients and 24 healthy controls were enrolled in this study. We analyzed mRNA expression of TRIM21, type I IFN, and IFN-inducible genes in peripheral blood mononuclear cell (PBMC). The protein levels of IRFs were assessed by Western blotting in PBMCs cultured with or without MG-132.

Results: The expression of TRIM21 mRNA and protein was significantly higher in SLE PBMCs as compared to healthy controls. There was a correlation between TRIM21 mRNA expression and SLE activities. In contrast to a negative correlation between mRNA expression level of TRIM21 and those of type I IFNs in healthy controls, we found a positive correlation between them in anti-TRIM21 antibody-positive SLE patients. Neither positive nor negative correlation was observed in the autoantibody-negative SLE patients. Western-blotting analysis revealed impaired ubiquitin-dependent proteasomal degradation of IRFs in SLE PBMCs.

Conclusion: Our study showed ubiquitin-dependent proteasomal degradation of IRFs was impaired in anti-TRIM21 antibody-dependent and -independent fashions, leading to amplification of IFN signature in SLE.
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http://dx.doi.org/10.1080/14397595.2018.1436028DOI Listing
November 2018

Beneficial use of serum ferritin and heme oxygenase-1 as biomarkers in adult-onset Still's disease: A multicenter retrospective study.

Mod Rheumatol 2018 Sep 11;28(5):858-864. Epub 2018 Jan 11.

l Yokohama City University School of Medicine , Kanagawa , Japan.

Background: Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD.

Methods: Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis.

Results: Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis.

Conclusion: We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi's Criteria.
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http://dx.doi.org/10.1080/14397595.2017.1422231DOI Listing
September 2018

Clinical manifestations of Behçet's disease depending on sex and age: results from Japanese nationwide registration.

Rheumatology (Oxford) 2017 11;56(11):1918-1927

Department of Ophthalmology and Visual Science.

Objective: This report aimed to scrutinize the prevalence of Behçet's disease (BD)-related clinical manifestations based on age- and sex-specific subgroups using a Japanese nationwide registration database.

Methods: The database of newly registered BD was obtained from the Japanese Ministry of Health, Labour and Welfare. Patients who met the International Criteria for Behçet's Disease were selected and analysed.

Results: Among 6627 International Criteria for Behçet's Disease cases, 2651 (40.0%) were men and 3976 (60.0%) were women with a median age of 39 years (interquartile range: 31-50 years). Ocular lesion was more common in male [odds ratio (male: female) 2.64 (95% CI: 2.35, 2.95, P < 0.001)] and genital ulceration was more common in female (odds ratio = 0.29, 95% CI: 0.25, 0.32, P < 0.001). Ocular lesion (P < 0.001), arthritis (P < 0.001) and vascular lesions (P < 0.001) were more frequently observed in elderly registered patients. Contrarily, genital ulceration (P < 0.001), epididymitis of males (P = 0.023) and oral ulceration (P = 0.003) were more common in younger patients. Simultaneous assessment of sex and age revealed that male predominance of ocular involvement was found in the young adult generation, but not in patients over 70 year of age. A female predominance of genital ulcer was prominently observed in patients 20-59 year of age; however, the sex difference was not found in patients over 60 years of age. Sensitivity analysis using International Study Group criteria replicated the results.

Conclusion: We showed that clinical phenotype in early phase of BD was different depending on onset age and sex.
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http://dx.doi.org/10.1093/rheumatology/kex285DOI Listing
November 2017

Distinct clinical features between acute and chronic progressive parenchymal neuro-Behçet disease: meta-analysis.

Sci Rep 2017 08 31;7(1):10196. Epub 2017 Aug 31.

Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Neuro-Behçet's disease (NBD) is subcategorized into parenchymal-NBD (P-NBD) and non-parenchymal-NBD types. Recently, P-NBD has been further subdivided into acute P-NBD (A-P-NBD) and chronic progressive P-NBD (CP-P-NBD). Although an increasing number of studies have reported the various clinical features of A-P-NBD and CP-P-NBD over the last two decades, there was a considerable inconsistency. Two investigators systematically searched four electrical databases to detect studies that provided sufficient data to assess the specific characteristics of A-P-NBD and CP-P-NBD. All meta-analysis was carried out by employing the random-model generic inverse variance method. We included 11 reports consisted of 184 A-P-NBD patients and 114 CP-P-NBD patients. While fever (42% for A-P-NBD, 5% for CP-P-NBD, p < 0.001, I = 93%) was more frequently observed in A-P-NBD cases; sphincter disturbances (9%, 34%, P = 0.005, I = 87%), ataxia (16%, 57%, P < 0.001, I = 92%), dementia (7%, 61%, P < 0.001, I = 97%), confusion (5%, 18%, P = 0.04, I = 76%), brain stem atrophy on MRI (4%, 75%, P < 0.001, I = 98%), and abnormal MRI findings in cerebellum (7%, 54%, P = 0.02, I = 81%) were more common in CP-P-NBD. Cerebrospinal fluid cell count (94/mm, 11/mm, P = 0.009, I = 85%) was higher in A-P-NBD cases. We demonstrated that A-P-NBD and CP-P-NBD had clearly different clinical features and believe that these data will help future studies investigating P-NBD.
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http://dx.doi.org/10.1038/s41598-017-09938-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579041PMC
August 2017

Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.

Nat Genet 2017 Mar 6;49(3):438-443. Epub 2017 Feb 6.

Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.

We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 × 10) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker at IL1A-IL1B, was associated with both decreased IL-1α and increased IL-1β production. ABO non-secretor genotypes for two ancestry-specific FUT2 SNPs showed strong disease association (P = 5.89 × 10). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility.
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http://dx.doi.org/10.1038/ng.3786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369770PMC
March 2017

Clinical and Genetic Features of Patients With TNFRSF1A Variants in Japan: Findings of a Nationwide Survey.

Arthritis Rheumatol 2016 11;68(11):2760-2771

Kyushu University Beppu Hospital, Beppu, Japan.

Objective: To elucidate the clinical and genetic features of patients with TNFRSF1A variants in Japan using data obtained from a nationwide survey conducted by the Ministry of Health, Labor, and Welfare of Japan study group for tumor necrosis factor receptor-associated periodic syndrome (TRAPS).

Methods: Inquiries were sent to 2,900 departments of internal medicine and pediatrics in all hospitals with more than 200 beds in Japan, asking whether they had patients in whom TRAPS was suspected. Genetic tests for TNFRSF1A, MEFV, and MVK were performed on 169 patients. Cell surface expression of TNFRSF1A variants was assessed using 293T cells.

Results: Ten patients from 10 independent families were found to have TNFRSF1A variants. We collected clinical and genetic information on 41 additional patients with TNFRSF1A variants and symptoms of inflammation from 23 independent families; 17 of these patients had not been described in the literature. The common clinical features of Japanese patients were fever of >38°C (100% of patients), arthralgia (59%), and rash (55%). The prevalence of abdominal pain (36%), myalgia (43%), and amyloidosis (0%) was significantly lower in Japanese patients than in Caucasian patients. The most common variant was T61I (appearing in 49% of patients), and it was identified in 7 of 363 healthy controls. Defects in cysteine residues and the T50M variant were associated with decreased cell surface expression, while other variants, including T61I, were not.

Conclusion: Patients with TNFRSF1A variants are very rare in Japan, as in other countries, but there are a number of clinical and genetic differences between Japanese and Caucasian patients. The pathogenic significance of the T61I variant remains unclear.
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http://dx.doi.org/10.1002/art.39793DOI Listing
November 2016

Continuous evolution of clinical phenotype in 578 Japanese patients with Behçet's disease: a retrospective observational study.

Arthritis Res Ther 2016 10 3;18(1):217. Epub 2016 Oct 3.

Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-Ku, Yokohama, 236-0004, Japan.

Background: It has been suggested that the phenotypes of Behçet's disease (BD) in Japan are changing. To ask whether the evolution of BD holds true in recent-onset cases in Japan, we performed a retrospective study.

Methods: We reviewed the records of 578 patients with BD who met the 1987 revised diagnostic criteria of the Behçet's disease research committee of Japan. The patients were divided into three groups based on the date of disease onset. We compared the demography, clinical features, and treatments among them with or without adjustment for the observation period. Patients having oral ulcers, genital ulcers, regional skin involvement, and uveitis are categorized as having complete-type BD, and the associated factors were determined by univariate and multivariate logistic regression analyses.

Results: Male patients had a higher propensity for uveitis and central nervous system (CNS) involvement, whereas female patients had higher rates of genital ulcers and arthritis. We found a significant trend in reduction of complete-type, genital ulcer, HLA-B51 carriers, and increment of gastrointestinal BD over time. Multiple regression analysis identified HLA-B51 positivity, earlier date of disease onset, and younger age of onset as independently associated with complete-type BD. Although treatments had been also chronologically changed, the causative relationship between therapeutic agents and phenotypical changes was not determined from the study.

Conclusion: The present study revealed that phenotypical evolution was characterized by decreased incidence of the complete type and increment of gastrointestinal involvement in Japanese patients with BD during the last 30 years.
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http://dx.doi.org/10.1186/s13075-016-1115-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048408PMC
October 2016

Non-IgG4-related Multifocal Fibrosclerosis.

Intern Med 2016 1;55(17):2497-502. Epub 2016 Sep 1.

Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Japan.

Multifocal fibrosclerosis (MFS), which causes systemic and chronic connective tissue inflammation, has been associated with IgG4 and regarded as an identical entity with "IgG4-related disease (IgG4-RD)". Although a few cases of MFS mimicking IgG4-RD histopathologically, despite the absence of a serum IgG4 elevation and IgG4-positive plasma cell infiltration, have been reported, there is, so far, little information regarding such exceptional cases. We herein demonstrate a case of non-IgG4-related MFS presenting with periaortitis and parotiditis, whose histological findings were consistent with IgG4-RD despite the absence of elevated serum and tissue IgG4 levels.
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http://dx.doi.org/10.2169/internalmedicine.55.6297DOI Listing
March 2017

On-demand ultrasonography assessment in the most symptomatic joint supports the 8-joint score system for management of rheumatoid arthritis patients.

Mod Rheumatol 2017 Mar 13;27(2):257-265. Epub 2016 Jul 13.

a Department of Hematology and Clinical Immunology , Yokohama City University School of Medicine , Yokohama , Japan.

Objectives: To investigate whether on-demand ultrasonography (US) assessment alongside a routine examination is useful in the management of rheumatoid arthritis (RA).

Methods: US was performed in eight (bilateral MCP 2, 3, wrist and knee) joints as the routine in a cumulative total of 406 RA patients. The most symptomatic joint other than the routine joints was additionally scanned. Power Doppler (PD) and gray-scale images were scored semiquantitatively. Eight-joint scores were calculated as the sum of individual scores for the routine joints.

Results: The most symptomatic joint was found among the routine joints in 209 patients (Group A) and in other joints in 148 (Group B). The PD scores of the most symptomatic joint correlated well with the 8-joint scores in Group A (r = 0.66), but not in Group B (r = 0.33). The sensitivity and specificity of assessment of the most symptomatic joint for routine assessment positivity were high (84.0% and 100%, respectively) in Group A, but low (50.0% and 61.8%, respectively) in Group B. Additional examination detected synovitis in 38% of Group B with negative results in the routine.

Conclusions: On-demand US assessment in the most symptomatic joint, combined with the routine assessment, is useful for detecting RA synovitis.
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http://dx.doi.org/10.1080/14397595.2016.1206173DOI Listing
March 2017

Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: Efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study.

Medicine (Baltimore) 2016 Jun;95(24):e3863

Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara Department of Internal Medicine, Teikyo University School of Medicine, Tokyo Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo Mitsubishi Tanabe Pharma Corporation, Osaka Yokohama City University, Yokohama, Japan.

Behçet disease (BD) is a multisystem disease associated with a poor prognosis in cases of gastrointestinal, neurological, or vascular involvement. We conducted a multicenter, prospective, open-label, single-arm phase 3 study to determine the efficacy, safety, and pharmacokinetics of infliximab (IFX) in BD patients with these serious complications who had displayed poor response or intolerance to conventional therapy.IFX at 5 mg/kg was administered to 18 patients (11 intestinal BD, 3 neurological BD [NBD], and 4 vascular BD [VBD]) at weeks 0, 2, and 6 and every 8 weeks thereafter until week 46. In patients who showed inadequate responses to IFX after week 30, the dose was increased to 10 mg/kg. We then calculated the percentage of complete responders according to the predefined criteria depending on the symptoms and results of examinations (ileocolonoscopy, brain magnetic resonance imaging, computed tomography angiography, positron emission tomography, cerebrospinal fluid, or serum inflammatory markers), exploring the percentage of complete responders at week 30 (primary endpoint).The percentage of complete responders was 61% (11/18) at both weeks 14 and 30 and remained the same until week 54. Intestinal BD patients showed improvement in clinical symptoms along with decrease in C-reactive protein (CRP) levels after week 2. Consistently, scarring or healing of the principal ulcers was found in more than 80% of these patients after week 14. NBD patients showed improvement in clinical symptoms, imaging findings, and cerebrospinal fluid examinations. VBD patients showed improvement in clinical symptoms after week 2 with reductions in CRP levels and erythrocyte sedimentation rate. Imaging findings showed reversal of inflammatory changes in 3 of the 4 VBD patients. Irrespective of the type of BD, all patients achieved improvement in quality of life, leading to the dose reduction or withdrawal of steroids. IFX dose was increased to 10 mg/kg in 3 intestinal BD patients, resulting in the improvement of clinical symptoms, CRP levels, and visual analogue scale score. Safety and pharmacokinetics profiles were comparable to those in patients with rheumatoid arthritis or Crohn disease. These findings support IFX as a new therapeutic option for patients with intestinal BD, NBD, or VBD.
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http://dx.doi.org/10.1097/MD.0000000000003863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998455PMC
June 2016

Hyper-recovery of platelets after induction therapy is a predictor of relapse-free survival in acute myeloid leukemia.

Leuk Lymphoma 2017 01 7;58(1):104-109. Epub 2016 Jun 7.

a Department of Internal Medicine and Clinical Immunology , Yokohama City University Graduate School of Medicine , Yokohama, Japan.

We verified the association between standard clinical and laboratory variables and the risk of relapse in acute myeloid leukemia (AML), which led us to retrospectively examine the effect of regeneration of hematopoiesis in patients with newly diagnosed AML. We used data from 230 patients who obtained remission after cytarabine-based induction chemotherapy. Platelet counts ≥500 × 10/L and hemoglobin levels ≥9 g/dL on day 28 after treatment initiation were significantly associated with relapse-free survival (RFS) rate, conferring respective multivariate risk ratios of 0.38 (95% CI: 0.18-0.79) and 0.60 (95% CI: 0.40-0.89) for the occurrence of relapse or death. No disease relapse occurred in core binding factor leukemia patients whose platelet counts recovered ≥500 × 10/L at 28 days after therapy initiation. We conclude that regeneration of hematopoiesis, especially platelet hyper-recovery, after induction chemotherapy is a significant predictor of RFS in patients with AML.
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http://dx.doi.org/10.1080/10428194.2016.1190969DOI Listing
January 2017

Retrospective Study of Incidence and Prognostic Significance of Eosinophilia after Allogeneic Hematopoietic Stem Cell Transplantation: Influence of Corticosteroid Therapy.

Turk J Haematol 2016 Sep 18;33(3):196-201. Epub 2016 Apr 18.

Kanagawa Cancer Center, Department of Hematology, Yokohama, Japan, Phone: 81-45-391-5761, E-mail:

Objective: The clinical significance of eosinophilia after allogeneic hematopoietic stem cell transplantation is controversial. This study aimed to retrospectively study the impact of eosinophilia on the outcome of allogeneic hematopoietic stem cell transplantation by taking into account the influence of corticosteroid therapy.

Materials And Methods: We retrospectively studied 204 patients with acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome who underwent allogeneic hematopoietic stem cell transplantation from January 2001 to December 2010.

Results: The median age was 43 years (minimum-maximum: 17-65 years). Myeloablative conditioning was used in 153 patients and reduced intensity conditioning was employed in 51 patients. Donor cells were from bone marrow in 132 patients, peripheral blood in 34, and cord blood in 38. Eosinophilia was detected in 71 patients and there was no significant predictor of eosinophilia by multivariate analysis. There was no relationship between occurrence of eosinophilia and the incidence or grade of acute graft-versus-host disease when the patients were stratified according to corticosteroid treatment. Although eosinophilia was a prognostic factor for 5-year overall survival by univariate analysis, it was not a significant indicator by multivariate analysis.

Conclusion: These results suggest that the clinical significance of eosinophilia in patients receiving allogeneic hematopoietic stem cell transplantation should be assessed with consideration of systemic corticosteroid administration.
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http://dx.doi.org/10.4274/tjh.2015.0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111464PMC
September 2016

Effect of adiponectin-encoding gene ADIPOQ single nucleotide polymorphisms +45 and +276 on serum lipid levels after antiretroviral therapy in Japanese patients with HIV-1-infection.

J Int Med Res 2016 Apr 1;44(2):297-306. Epub 2016 Feb 1.

Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.

Objectives: To investigate the association between single nucleotide polymorphisms (SNPs) in the adiponectin-encoding gene ADIPOQ and changes in serum lipid levels in HIV-1-infected patients after antiretroviral therapy (ART).

Methods: ART-naïve HIV-1-infected patients were recruited to this prospective analysis. SNP +45 and SNP +276 genotype was determined by direct sequencing. Multivariate linear regression analysis was performed to analyse the effects of genotype, and predisposing conditions on serum total cholesterol and triglyceride in the 4 months before and after ART initiation.

Results: The study enrolled 78 patients with HIV-1-infection (73 male, five female; age range 22-67 years). HIV-1 viral load ≥5 log10 copies/ml, baseline total cholesterol ≥160 mg/dl, and CD4(+) lymphocyte count <200/µl were associated with increased serum total cholesterol levels after ART initiation. Protease inhibitor treatment and body mass index ≥25 kg/m(2) were associated with increased triglyceride levels after ART initiation. There were no significant associations between SNP +45 or SNP +276 genotype and serum total cholesterol or triglyceride levels.

Conclusions: SNP +45 and SNP +276 genotype is not associated with changes in serum total cholesterol or triglyceride levels after ART initiation.
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http://dx.doi.org/10.1177/0300060515621444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580050PMC
April 2016

Prognostic value of pretransplant serum C-reactive protein in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation.

Int J Hematol 2016 Apr 20;103(4):444-52. Epub 2016 Jan 20.

Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan.

The impact of pre-transplant serum C-reactive protein (CRP) level on the outcome of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC allo-SCT) is unclear. This study retrospectively investigated 78 patients who underwent RIC allo-SCT between 2005 and 2013. The conditioning regimen consisted of fludarabine and melphalan with/without total body irradiation. The 3-year overall survival of high CRP (43.6 % of all patients) patients was significantly worse than that of normal CRP patients in whom CRP was ≤0.3 mg/dl (26.7 vs. 74.1 %, P < 0.001). Both the CRP level before transplantation and disease risk status were independent prognostic factors for overall survival by multivariate analysis. CRP was not a significant predictor of NRM by multivariate analysis (hazard ratio 3.2, 95 % confidence interval 0.8-13.1, P = 0.100). These results suggest that measuring the CRP level before transplantation can be useful to predicting the outcome of RIC allo-SCT.
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http://dx.doi.org/10.1007/s12185-016-1941-2DOI Listing
April 2016

Discontinuation of etanercept after achievement of sustained remission in patients with rheumatoid arthritis who initially had moderate disease activity-results from the ENCOURAGE study, a prospective, international, multicenter randomized study.

Mod Rheumatol 2016 Sep 23;26(5):651-61. Epub 2015 Dec 23.

k Division of Rheumatology , Department of Internal Medicine Keio University School of Medicine , Japan .

Objectives: To investigate the efficacy and safety of etanercept (ETN) in patients with rheumatoid arthritis (RA) with moderate disease activity and the possibility to discontinue ETN after achieving remission.

Methods: Multicenter, randomized, and open-label study was conducted in Japan and Korea. RA patients (disease duration <5 years) with moderate disease activity despite methotrexate (MTX) treatment were allocated to either MTX or ETN + MTX (Period 1) for 12 months. Patients who achieved sustained remission defined as DAS28 < 2.6 at both 6 and 12 months in the ETN + MTX group, were randomized to either continue or discontinue ETN for 12 months (Period 2).

Results: A total of 222 patients were enrolled in Period 1 and clinical remission was achieved in 106/157 (67.5%) and 5/28 (17.9%) patients in the ETN + MTX and MTX groups, respectively. In Period 2, sixty-seven patients were randomized and finally 28/32 (87.5%) and 15/28 (53.6%) patients who continued or discontinued ETN maintained clinical remission. Baseline disease activity and the presence of comorbid diseases influenced the maintenance of remission after ETN discontinuation.

Conclusions: ETN + MTX was efficient for RA patients with moderate disease activity into remission. After achieving sustained remission, a half of the patients who discontinued ETN could maintain remission for 1 year.
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http://dx.doi.org/10.3109/14397595.2015.1123349DOI Listing
September 2016

The effectiveness of sputum pH analysis in the prediction of response to therapy in patients with pulmonary tuberculosis.

PeerJ 2015 26;3:e1448. Epub 2015 Nov 26.

Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine , Yokohama , Japan.

Purpose. The predictive factor of response to antituberculous therapy has not been fully elucidated. Airway acidity has been thought to be a potential indicator of the bactericidal activity. Therefore, we hypothesized that monitoring airway acidity by measuring sputum pH could predict response to therapy. Methods. A total of 47 patients having newly diagnosed, smear-positive, active pulmonary tuberculosis were enrolled between October 2011 and March 2014. Sputum samples were serially analyzed before and after treatment. Eligible patients who initiated a standard 6-month treatment were monitored for the length of time to sputum smear and culture conversion. Results. There were 39 patients who completed a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide, and ethambutol therapy followed by a 4-month continuation phase of isoniazid and rifampicin. Although factors including age, cavitation, sputum grade, and use of an acid-suppressant were associated with initial low sputum pH in univariate analysis, multivariate analysis revealed that only age ≥61 years was a statistically important factor predicting low pH value (p = 0.005). Further outcome analysis showed that initial low sputum pH before treatment was the only factor significantly associated with shorter length of time to both sputum smear and culture conversion (p = 0.034 and 0.019, respectively) independent of the effects of age, sputum bacterial load, extent of lung lesion, and cavitation. Thus, initial low sputum pH indicated favorable response to anti-tuberculosis therapy. Conclusions. Measuring sputum pH is an easy and inexpensive way of predicting response to standard combination therapy in patients with pulmonary tuberculosis.
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http://dx.doi.org/10.7717/peerj.1448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671190PMC
December 2015

Chronic Use of Theophylline and Mortality in Chronic Obstructive Pulmonary Disease: A Meta-analysis.

Arch Bronconeumol 2016 May 21;52(5):233-8. Epub 2015 Nov 21.

Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japón; Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japón.

Background: Theophylline has been shown to improve respiratory function and oxygenation in patients with chronic obstruction pulmonary disease (COPD). However, the impact of theophylline on mortality in COPD patients has not been not sufficiently evaluated.

Method: Two investigators independently searched for eligible articles in 4 databases. The eligibility criterion for this meta-analysis was an original research article that provided a hazard ratio for theophylline for all-cause mortality of COPD patients. Both randomized controlled trials and observational studies were accepted. After we confirmed no substantial heterogeneity (I(2)<50%), the fixed-model method with generic inverse variance was used for meta-analysis to estimate the pooled hazard ratio.

Results: We screened 364 potentially eligible articles. Of the 364 articles, 259 were excluded on the basis of title and abstract, and 99 were excluded after examination of the full text. Our final analysis included 6 observational studies and no randomized controlled trials. One study reported 2 cohorts. The number of patients in each cohort ranged from 47 to 46,403. Heterogeneity (I(2)=42%, P=.11) and publication bias (Begg's test r=0.21, P=.662) were not substantial. Fixed-model meta-analysis yielded a pooled hazard ratio for theophylline for all-cause death of 1.07 (95% confidence interval: 1.02-1.13, P=.003).

Conclusion: This meta-analysis of 7 observational cohorts suggests that theophylline slightly increases all-cause death in COPD patients.
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http://dx.doi.org/10.1016/j.arbres.2015.02.021DOI Listing
May 2016

An Autopsy Case Report of Malignant Pleural Mesothelioma with Deciduoid Features.

Intern Med 2015 15;54(22):2915-7. Epub 2015 Nov 15.

Department of Respiratory Medicine, Yokohama City University Hospital, Japan.

Deciduoid mesothelioma is a rare variant of epithelioid mesothelioma. We experienced the case of a 73-year-old man with asbestos exposure who was diagnosed with malignant pleural mesothelioma with deciduoid features. He received chemotherapy containing six cycles of cisplatin and pemetrexed and survived for twenty-five months after the diagnosis. At autopsy, the final diagnosis was biphasic pleural mesothelioma. Cells with deciduoid features had mostly disappeared, and spindle cells markedly proliferated. To the best of our knowledge, this is the first autopsy case of malignant pleural mesothelioma with deciduoid features that exhibited a response to chemotherapy.
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http://dx.doi.org/10.2169/internalmedicine.54.4940DOI Listing
July 2016

Successful Engraftment and Durable Graft-versus-host Disease Control with Haploidentical Peripheral Blood and a Short-term Conditioning Regimen for Primary Graft Failure.

Intern Med 2015 1;54(21):2749-52. Epub 2015 Nov 1.

Department of Hematology, Yokohama City University Medical Center, Japan.

Primary graft failure occurred after cord blood transplantation for a patient with acute lymphoblastic leukemia. The second transplantation was performed using haploidentical peripheral blood. The conditioning regimen consisted of fludarabine (day -1; 30 mg/m(2)), cyclophosphamide (day -1; 2,000 mg/m(2)), and total body irradiation (day -1; 2 Gy). The immunosuppressants contained tacrolimus, prednisolone, and rabbit anti-thymocyte globulin (day -3 to -2; total dose: 3.75 mg/kg). The engraftment was confirmed on day 9. Both acute and chronic graft-versus-host disease were controllable. The present regimen appears to be suitable for immediate management, fast engraftment, and the durable control of complications.
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http://dx.doi.org/10.2169/internalmedicine.54.4809DOI Listing
May 2016

HO-1 inhibits IL-13-induced goblet cell hyperplasia associated with CLCA1 suppression in normal human bronchial epithelial cells.

Int Immunopharmacol 2015 Dec 24;29(2):448-453. Epub 2015 Oct 24.

Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Mucus hypersecretion and goblet cell hyperplasia are common features that characterize asthma. IL-13 increases mucin (MUC) 5AC, the major component of airway mucus, in airway epithelial cells. According to the literature, IL-13 receptor activation leads to STAT6 activation and consequent induction of chloride channel accessory 1 (CLCA1) gene expression, associated with the induction of MUC5AC. Heme oxygenase-1 (HO-1) is an enzyme that catalyzes oxidation of heme to biliverdin, and has anti-inflammatory and anti-oxidant properties. We examined the effects of HO-1 on mucin production and goblet cell hyperplasia induced by IL-13. Moreover, we assessed the cell signaling intermediates that appear to be responsible for mucin production. Normal human bronchial epithelial (NHBE) cells were grown at air liquid interface (ALI) in the presence or absence of IL-13 and hemin, a HO-1 inducer, for 14 days. Protein concentration was analyzed using ELISA, and mRNA expression was examined by real-time PCR. Histochemical analysis was performed using HE staining, andWestern blotting was performed to evaluate signaling transduction pathway. Hemin (4 μM) significantly increased HO-1 protein expression (p b 0.01) and HO-1 mRNA expression (p b 0.001). IL-13 significantly increased goblet cells, MUC5AC protein secretion (p b 0.01) and MUC5AC mRNA (p b 0.001), and these were decreased by hemin by way of HO-1. Tin protoporphyrin (SnPP)-IX, a HO-1 inhibitor, blocked the effect of hemin restoring MUC5AC protein secretion (p b 0.05) and goblet cell hyperplasia. Hemin decreased the expression of CLCA1 mRNA (p b 0.05) and it was reversed by SnPP-IX, but could not suppress IL-13-induced phosphorylation of STAT6 or SAM pointed domain-containing ETS transcription factor (SPDEF) and Forkhead box A2 (FOXA2) mRNA expression. In summary, HO-1 overexpression suppressed IL-13-induced goblet cell hyperplasia and MUC5AC production, and involvement of CLCA1 in the mechanism was suggested.
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http://dx.doi.org/10.1016/j.intimp.2015.10.016DOI Listing
December 2015

Clinical value of capsule endoscopy for detecting small bowel lesions in patients with intestinal Behçet's disease.

Dig Endosc 2016 Mar 28;28(2):179-85. Epub 2015 Oct 28.

Division of Gastroenterology and Hepatology.

Background And Aim: To evaluate the clinical value of capsule endoscopy (CE) in patients with intestinal Behçet's disease (BD).

Methods: The present study was a case-control pilot study conducted in intestinal BD patients and healthy volunteers. A total of 19 patients with intestinal BD (intestinal BD group) and 19 healthy volunteers (control group) matched for age and sex were enrolled. Frequency, number of small bowel lesions per subject, and Lewis score were comparatively evaluated between the two groups.

Results: Of the 19 patients with intestinal BD, 18 (94.7%) had reddened lesions, 15 (78.9%) had erosions, and nine (47.4%) had ulcers. There were significant differences in the frequency of reddened lesions (P < 0.0001), erosions (P < 0.0001) and ulcers (P = 0.0011) between the two groups. The difference in the number of small bowel lesions between the two groups was also statistically significant. The median Lewis score in the intestinal BD group was significantly higher than that in the control group (intestinal BD group 237 (0-768) vs. control group 8 (0-135); P < 0.0001). Analysis according to the location in the small bowel revealed that the frequency of ulcers tended to increase towards the distal intestine.

Conclusion: This is the first CE study conducted to examine small bowel involvement in intestinal BD patients. Our results suggest that CE evaluation is necessary, in addition to colonoscopy, in all intestinal BD patients.
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http://dx.doi.org/10.1111/den.12552DOI Listing
March 2016

Currently Used Low-Dose Pyrazinamide Does Not Increase Liver-Injury in the First Two Months of Tuberculosis Treatment.

Intern Med 2015 15;54(18):2315-20. Epub 2015 Sep 15.

Department of Pulmonology, Yokohama City University Graduate School of Medicine, Japan.

Objective: In the 1950s, a high-dose (40-70 mg/kg/day) of pyrazinamide (PZA), was reported to cause drug-induced liver injury (DILI) at an unacceptable frequency. It remains unclear whether adding PZA (Z) at the currently accepted low-dose (20-25 mg/kg/day) for two months to a regimen of isoniazid (H) + rifampicin (R) + ethambutol (E) actually increases the risk of DILI.

Method: Smear-positive tuberculosis patients were treated with daily HRE or HRZE regimen under direct observation. We used three independent models. Model 1 was analyzed with a multivariate Cox-analysis using a pre-matched cohort. Next, propensity score matching was conducted using the nearest neighbor method with caliper of 0.03. Models 2 and 3 were analyzed by univariate and multivariate Cox-analyses, respectively, with the matched cohort. DILI was assessed based on the guidelines of the American Thoracic Society.

Results: We reviewed the records of 383 patents (male, n=260; female n=123; mean age, 64±20 years). Among these patients, 75 patients were treated with HRE and 308 were treated with HRZE. DILI occurred in the first two months in 24% (18/75) and 8% (24/308) of the HRE-treated and HRZE-treated cases, respectively. In all three of the models, DILI was less frequent in patients treated with the HRZE regimen: Model 1, HR of 0.30 (95% confidence interval (CI) 0.14-0.68, p=0.004); Model 2, HR of 0.37 (95%CI 0.14-0.96, p=0.041); and Model 3, HR of 0.34 (95%CI 0.12-0.94, p=0.038).

Conclusion: The addition of the currently accepted low dose (20-25 mg/kg/day) of PZA to the HRE regimen did not increase the incidence of DILI during the first two months of treatment.
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http://dx.doi.org/10.2169/internalmedicine.54.5533DOI Listing
April 2016

Beta-2 microglobulin is a strong prognostic factor in patients with DLBCL receiving R-CHOP therapy.

Leuk Res 2015 Aug 29. Epub 2015 Aug 29.

Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.

Useful prognostic markers for patients with diffuse large B cell lymphoma (DLBCL) have been reported. To identify which biomarker best predicts the prognosis of patients with DLBCL, we performed a retrospective study that included 319 DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy between 2003 and 2012. We assessed the prognostic significance of six biomarkers [lactate dehydrogenase, soluble interleukin-2 receptor, thymidine kinase activity, beta-2 microglobulin (B2M), C-reactive protein, and ferritin] and representative clinical characteristics using progression-free survival (PFS) as the endpoint. The study group included 181 men and 138 women with a median age of 63 years (range, 22-89 years). In a multivariate analysis, the serum B2M level most strongly correlated with PFS (hazard ratio, 2.11; P=0.04). In a univariate analysis, patients with serum B2M levels >1.75μg/mL (n=210) had a worse 3-year PFS rate (71.2%) than those with B2M levels <1.75μg/mL (n=109; 90.0%). Therefore, serum B2M level at the time of diagnosis is a useful prognostic indicator in DLBCL patients receiving R-CHOP.
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http://dx.doi.org/10.1016/j.leukres.2015.08.016DOI Listing
August 2015

Impact of Corticosteroids on Mortality in Patients with Acute Respiratory Distress Syndrome: A Systematic Review and Meta-analysis.

Intern Med 2015 ;54(12):1473-9

Objective: The impact of corticosteroids on acute respiratory distress syndrome (ARDS) mortality remains controversial following the publication of numerous trials, observational studies and meta-analyses. An updated meta-analysis is warranted, as a few original studies on this topic have been published since the last meta-analysis.

Methods: We searched for eligible articles using four databases. In particular, we included full-length original articles providing sufficient data for evaluating the impact of corticosteroid treatment on adult ARDS mortality in the form of odds ratios. A fixed model with the confidence interval method was used. An assessment of publication bias and sensitivity analyses were also conducted.

Results: We included 11 of 185 articles. The pooled odds ratio for corticosteroids with respect to all-cause mortality involving 949 patients was 0.77 [95% confidence interval (CI): 0.58-1.03, p=0.079] with strong heterogeneity(I2=70%, p<0.001). The results of the sensitivity analysis, Begg-Kendall test (τ=0.53, p=0.024)and funnel plot consistently suggested the existence of strong publication bias. After six potentially unpublished cohorts were filled using Duval's trim and fill method, the pooled odds ratio shifted to 1.11 (95% CI0.86-1.44, p=0.427). In addition, the sensitivity analyses suggested that corticosteroid treatment has a different impact on mortality depending on the comorbidities and trigger events.

Conclusion: We were unable to confirm, based on the data of published studies, the favorable impact of corticosteroid therapy on mortality in overall ARDS cases. Published articles exhibit strong publication bias,and previous meta-analyses may be affected by this publication bias. Further research focusing on pathophysiology- or trigger event-specific ARDS is anticipated.
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http://dx.doi.org/10.2169/internalmedicine.54.4015DOI Listing
January 2016
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