Clinical effectiveness of iguratimod based on real-world data of patients with rheumatoid arthritis.

OBJECTIVES: Iguratimod (IGU) is a conventional synthetic disease-modifying drug that has been approved based on its additive effects with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). The objective of the study is to establish the effectiveness of IGU with versus IGU without MTX irrespective of whether MTX is well tolerated or not by the patients. METHODS: Disease activity scores in 177 RA patients treated using IGU were retrospectively evaluated at baseline and after 4, 12, and 24 weeks, and adverse events (AEs) were noted. RESULTS: IGU reduced the disease activity parameters, disease activity score (DAS)-ESR, DAS-CRP, the simplified disease activity index (SDAI), and clinical disease activity index (CDAI) in the concomitant MTX and non-MTX, female and male, and young and elderly patient groups after 24 weeks. Multivariate analysis demonstrated that IGU was more effective with concomitant MTX and in elderly and male patients. Severe AEs were observed only in the elderly group: two cases of pneumonia, 1 of pneumocystis pneumonia, 1 of heart failure, and 1 of salivary gland adenoma. CONCLUSIONS: IGU is effective for RA, especially with concomitant MTX, and in elderly and male patients. Key Points • Iguratimod is effective for RA, especially with concomitant MTX, and in elderly and male patients. • Since all serious adverse events were in the elderly group in this study, sufficient monitoring for adverse events, especially for elderly RA patients, is needed during iguratimod therapy.

Comprehensive Analysis of Antibodies Induced by Vaccination with 4 Kinds of Avian Influenza H5N1 Pre-Pandemic Vaccines.

Four kinds of avian-derived H5N1 influenza virus, A/Vietnam/1194/2004 (Clade 1), A/Indonesia/5/2005 (Clade 2.1), A/Qinghai/1A/2005 (Clade 2.2), and A/Anhui/1/2005 (Clade 2.3), have been stocked in Japan for use as pre-pandemic vaccines. When a pandemic occurs, these viruses would be used as vaccines in the hope of inducing immunity against the pandemic virus. We analyzed the specificity of antibodies (Abs) produced by B lymphocytes present in the blood after immunization with these vaccines. Eighteen volunteers took part in this project. After libraries of Ab-encoding sequences were constructed using blood from subjects vaccinated with these viruses, a large number of clones that encoded Abs that bound to the virus particles used as vaccines were isolated. These clones were classified into two groups according to the hemagglutination inhibition (HI) activity of the encoded Abs. While two-thirds of the clones were HI positive, the encoded Abs exhibited only restricted strain specificity. On the other hand, half of the HI-negative clones encoded Abs that bound not only to the H5N1 virus but also to the H1N1 virus; with a few exceptions, these Abs appeared to be encoded by memory B cells present before vaccination. The HI-negative clones included those encoding broadly cross-reactive Abs, some of which were encoded by non-VH1-69 germline genes. However, although this work shows that various kinds of anti-H5N1 Abs are encoded by volunteers vaccinated with pre-pandemic vaccines, broad cross-reactivity was seen only in a minority of clones, raising concern regarding the utility of these H5N1 vaccine viruses for the prevention of H5N1 pandemics.

High Dose Prednisolone Lowers Plasma Glycated Albumin Levels Compared to Actual Glycemic Control: A Retrospective Observational Study.

INTRODUCTION: Glycated hemoglobin (A1c) and glycated albumin (GA) are often used as indicators of glycemic control. In this study, we determined whether prednisolone (PSL) administration lowers plasma GA. METHODS: We investigated the factors affecting GA using multivariate analysis in 48 subjects with connective tissue diseases (CTDs). RESULTS: Multiple regression analysis of GA showed that the dose of PSL [ß = - 1.36; 95% confidence interval (CI) - 2.59 to - 0.14; p = 0.03], age (ß = 0.06; 95% CI 0.03-0.09; p < 0.001), body mass index (BMI) (ß = - 0.14; 95% CI - 0.28 to - 0.01; p = 0.042), and A1c (ß = 1.4; 95% CI 0.38-2.42; p = 0.008) significantly correlated with GA (adjusted R2 = 0.518). Moreover, GA levels adjusted for age, sex, BMI, plasma albumin (Alb) and creatinine (Cre), and A1c in the subjects taking ≥ 5 mg PSL was significantly lower than those in those taking < 5 mg PSL. Finally, the dose of PSL (as a continuous variable) was negatively correlated with GA adjusted for age, sex, BMI, Alb, Cre, and A1c. CONCLUSION: High dose (≥ 5 mg) PSL reduces GA concentration more than glycemia.

Three Types of Broadly Reacting Antibodies against Influenza B Viruses Induced by Vaccination with Seasonal Influenza Viruses.

We analyzed the antibody (Ab) repertoire against influenza B viruses induced by vaccination with seasonal influenza viruses in one individual who had never been vaccinated until 2009. The vaccine used in this study comprised B/Massachusetts/2/2012 (Yamagata lineage), A/Texas/50/2012 (H3N2), and A/California/7/2009 (H1N1). One month after the subject received two vaccinations, blood (200 ml) was obtained and peripheral mononuclear cells were prepared, and a large Ab library was constructed using phage display technology. The library was screened with HA-enriched fraction of B/Massachusetts/2/2012 and B/Brisbane/60/2008 (Victoria lineage) virus, and a total of 26 Abs that potentially bound to hemagglutinin (HA) molecules were isolated. Their binding activities to six influenza B viruses, three of Yamagata lineage and three of Victoria lineage, and two influenza A viruses, H1N1 and H3N2, were examined. The Abs showed cross-reactivity at three different levels. The first type bound to all Yamagata lineage viruses. The second type bound to both Yamagata and Victoria lineage viruses. The third type bound to both influenza A and B viruses. These results indicate that common epitopes exist on HA molecules of influenza virus at various levels, and humans have capability to produce Abs that bind to such common epitopes.

The Level of IgA Antibodies to Endothelial Cells Correlates with Histological Evidence of Disease Activity in Patients with Lupus Nephritis.

Anti-endothelial cell antibodies (AECA) are frequently detected in patients with systemic lupus erythematosus (SLE), but their pathological role remains unclear. We recently developed a solubilized cell surface protein capture enzyme-linked immunosorbent assay (CSP-ELISA) to detect antibodies against membrane proteins involved in autoimmune reactions. In this study, sera from 51 patients with biopsy-proven lupus nephritis (LN), 25 with SLE without renal involvement (non-LN SLE), 42 disease control (DC) subjects, and 80 healthy control (HC) subjects were tested for IgG- and IgA-AECA for human umbilical vein endothelial cells (HUVEC) and human glomerular EC (HGEC) by using CSP-ELISA. IgG- and IgA-AECA titers were significantly higher in LN and non-LN SLE patients than in the DC or HC (P < 0.001) groups. IgG- and IgA-AECA titers for HUVEC corresponded well with those for HGEC. The IgA-AECA level correlated with the SLE disease activity index and with histological evidence of active lesions (cellular proliferations, hyaline thrombi and wire loops, leukocytic infiltration, and fibrinoid necrosis) in LN patients (P < 0.001). The sensitivity of IgA-AECA as a diagnostic test for histological evidence of active lesions in LN patients was 0.92, with a specificity of 0.70. The significant correlation of IgA-AECA with glomerular hypercellularity indicates that IgA-AECA are associated with endothelial damage in LN.

Intrathecal administration of colistin for meningitis due to New Delhi metallo-ß-lactamase 1(NDM-1)-producing Klebsiella pneumoniae.

Infection by bacteria carrying New Delhi metallo-ß-lactamase 1 (NDM-1) is becoming a global health problem. We report a case of meningitis caused by NDM-1-producing Klebsiella pneumoniae, for which intrathecal administration of colistin was curative. A previously healthy 38-year-old Japanese man, who lived in Hyderabad, India, suddenly collapsed and was brought to a local hospital. He was diagnosed with subarachnoid hemorrhage and underwent emergency surgery which included partial skull removal. Approximately 1 month after surgery, he was repatriated to Japan and was admitted to our institution with information that he had been treated for multi-drug resistant Acinetobacter infection with colistin. A week after admission, he developed aspiration pneumonia due to NDM-1-producing K. pneumoniae, which was successfully treated by intravenous (IV) administration of colistin. Subsequently, he underwent a surgical procedure to repair his skull defect. He developed high-grade fever and altered mental status on postoperative day 2. NDM-1-producing K. pneumoniae was identified in the cerebrospinal fluid, establishing the diagnosis of meningitis. Although IV colistin was only partially effective, intrathecal colistin (10 mg daily by lumbar puncture for 14 days) successfully eradicated the meningitis. Because of economic globalization, NDM-1-producing bacteria may be brought to Japan by those who are repatriated after sustaining critical illnesses and being treated in foreign countries. This report may provide useful information on the treatment of central nervous system infection by NDM-1-producing bacteria.

Quantitative diagnosis of connective tissue disease-associated interstitial pneumonia using thoracic computed tomography images.

Patients with polymyositis (PM) or dermatomyositis (DM) frequently show interstitial pneumonia (IP), which is sometimes rapidly progressive or resistant to treatment, thereby significantly affecting the prognosis. The diagnosis and response evaluation of IP are commonly performed qualitatively based on imaging findings, which may cause disagreement among rheumatologists in the evaluation of early lesions and atypical interstitial changes. To determine whether IP could be diagnosed in a quantitative manner during the early stage of PM/DM using a workstation that allows quantitative image processing. Thoracic computed tomography (CT) images of 20 PM/DM patients were reconstructed into a three-dimensional (3D) image using an image processing workstation. The CT values of the constituent voxels were arranged in a histogram of -1000 to +1000 Hounsfield units (HU). The most frequent lung field density was -900 to -801 HU, and relative size was as follows: IP (+) group 0.45 and IP (-) group 0.53. Between -1000 and -701 HU, relative size was not significantly different between the IP (+) group and IP (-) group. Between -700 and -1 HU, the relative size of the lung field was significantly larger in the IP (+) than in the IP (-) group, demonstrating its IP-diagnosing ability. Particularly, within the range from -700 to -301 HU, the macroscopically-assessed ground glass opacity was consistent with the CT value, which, in turn, was closely correlated with KL-6, the pre-existing marker for IP diagnosis. The results of this study may lead to the establishment of quantitative methods of evaluating IP and possible elucidation of the pathogenesis of IP.

Successful treatment of septic shock due to New Delhi metallo-ß-lactamase-1-producing Klebsiella pneumoniae in a patient transferred from India to Japan.

CASE: Here we report the fifth case of New Delhi metallo-ß-lactamase-1-producing Enterobacteriaceae infection in Japan. A 39-year-old Japanese man suffered a subarachnoid hemorrhage due to rupture of aneurysm in India. Once he was deemed stable enough, he was transferred from a hospital in India to our hospital in Japan. On day 5 after transfer, the patient suddenly developed septic shock and multidrug-resistant Klebsiella pneumoniae was isolated from a blood culture. OUTCOME: Treatment with colistin and high-dose meropenem as well as organ support were initiated, resulting in successful resolution of septic shock. This K. pneumoniae was shown to carry blaNDM-1 by polymerase chain reaction analysis. CONCLUSION: Our case suggests that New Delhi metallo-ß-lactamase-1-producing bacteria could be introduced into Japan easily. It is important to apply strict surveillance and infection control measures to prevent the spread of carbapenem resistance genes to Enterobacteriaceae in Japan.

Stressors and rheumatoid arthritis: changes in stressors with advances in therapeutic agents.

The significance of evaluations of stressors in rheumatoid arthritis (RA) patients was investigated from the perspective of holistic medicine. The subjects were RA patients treated in the rheumatology outpatient clinic. They included 30 patients from 1987, 30 from 2002, and 137 from 2009. To investigate the specific causes of stress, the patients were asked the question, "What do you feel is your strongest stressor?" The same patients also underwent psychological testing and was examined the disease activity. Pain was the strongest stressor in RA patients in 1987, 2002, and 2009. However, the percentage of patients citing pain as their major stressor was decreasing with each year. CRP was significantly lower in 2009 than in 2002. CRP was also significantly lower in patients who used biologics than in patients who did not. In 2009, DAS28-CRP was significantly higher in patients whose largest stressor was pain than in patients whose largest stressor was another factor. In 2009, the values for both state anxiety and trait anxiety were significantly higher in patients who said that they had stressors than in those who said they did not. The strongest stressor in RA patients was pain. However, the percentage decreased over the years with lower disease activity from advances in therapeutic agents such as biologics. Meanwhile, stressors other than pain were the same or somewhat increased, and they were related to anxiety or depression. Understanding stressors in RA is thus important in treating RA patients.

Autoantibodies directed against labile epitopes on cell surface proteins in autoimmune disease patients: proposal of a novel ELISA for the detection of anti-endothelial cell antibodies.

This article describes a novel method for detecting anti-endothelial cell antibodies (AECAs). Sera from patients with systemic vasculitis or inflammatory conditions have been reported to contain antibodies (Abs) that bind to endothelial cells (EC), i.e., AECAs. AECAs are known to play immunogenic effects by triggering EC activation and vascular damage, but the immunopathological role of AECAs is not clear. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting have previously been used for detecting target antigens of AECAs. However, we assumed that these methods are not appropriate for searching genuine target antigens (Ags) on cell surface, and developed a novel solubilized cell surface protein-capture ELISA (CSP-ELISA). Ags were obtained as cell surface proteins from the plasma membrane of human umbilical vein endothelial cells (HUVECs); these cell surface proteins were biotinylated, solubilized with detergent, and captured on ELISA wells coated with NeutrAvidin™ biotin binding protein (NeuAvi). AECA titers in serum from 126 autoimmune disease patients and 122 healthy donors were tested. AECAs were detected in 28 of 36 (78%) of systemic lupus erythematosus (SLE) patients; in 13 of 16 (81%) of mixed connective tissue disease (MCTD) patients; and in 5 of 9 (56%) of systemic sclerosis (SSc) patients. Relatively weak denaturation of antigens on ELISA wells caused loss of binding of these autoantibodies (autoAbs). Thus, this newly developed CSP-ELISA method enables the detection of Abs to the labile epitopes of autoantigens (autoAgs) such as membrane proteins, and this method is generally applicable to various kinds of membrane proteins and the Abs against them. We propose CSP-ELISA for measuring AECAs in serum samples for routine laboratory testing.

Long-term safety and efficacy of ambrisentan in Japanese adults with pulmonary arterial hypertension.

OBJECTIVE: To investigate the safety and efficacy of long-term administration of ambrisentan in Japanese adults with pulmonary arterial hypertension (PAH). RESEARCH DESIGN AND METHODS: In this open-label extension of a preceding multicenter dose-escalation study, 21 Japanese patients with PAH received treatment with 5 or 10 mg of ambrisentan once daily and were comprehensively evaluated every 12 weeks. The primary endpoint was the safety of long-term ambrisentan administration, as defined by the incidence and severity of adverse events. The secondary (efficacy) endpoints were change in exercise capacity (as indicated by 6-minute walk distance), World Health Organization functional class, Borg dyspnea index, plasma brain natriuretic peptide level, cardiopulmonary hemodynamics, and time to clinical worsening of PAH. CLINICAL TRIAL REGISTRATION: NCT00554619. RESULTS: The mean total duration of treatment (i.e., including the preceding dose-escalation study) was approximately 139 weeks. There were fewer adverse events related to ambrisentan in this study than in the preceding study, and we identified no new safety signals that might preclude the long-term use of ambrisentan among Japanese adults with PAH. Improvements observed in efficacy endpoints in the preceding study were maintained in the present study. LIMITATIONS: This study did not include a control group and lacked the statistical power to reach definite conclusions regarding the efficacy of ambrisentan. CONCLUSION: Our results suggest that long-term administration of ambrisentan is well tolerated and efficacious for Japanese adults with PAH.

Distributions of calcitonin gene-related peptide and substance P in the human maxillary sinus of Japanese cadavers.

BACKGROUND: Substance P (SP) and calcitonin gene-related peptide (CGRP) are released by the nociceptive sensory nerve and are involved in blood flow, pain and inflammation in the nasal mucosa. The purpose of this study was to assess the distribution of the SP and CGRP nerve fibres related to blood supply within human Schneiderian membrane of the maxillary sinus (MS). MATERIAL AND METHODS: In this study, the MS from Japanese cadavers was examined by whole-mount immunohistochemistry. Human male cadavers (ranging in age from 80 to 90 years) were used in this study. RESULTS: SP- and CGRP-positive fibres were found around large vessels of the medialis superior alveolar branches and also within the floor region of the MS. The floor region of the MS was composed of complex branches of these fibres. CONCLUSION: Our results give useful information for surgical sinus floor elevation in this region of the MS. These anatomical features may assist in the execution of a successful surgical procedure.

Pulmonary arterial hypertension in connective tissue diseases.

Pulmonary hypertension (PH) was found to be the primary cause of death in mixed connective tissue disease (MCTD). This led to investigation of the prevalence of PH in other connective tissue diseases (CTD). In 1998, the Ministry of Health and Welfare's MCTD Research Committee revealed complication of PH diagnosed by physicians in 5.02% MCTD patients, 0.90% systemic lupus erythematosus patients, 2.64% systemic sclerosis patients, and 0.56% polymyositis/dermatomyositis patients. These results have been supported by a similar survey performed in North America. As quite a few rheumatologists find right heart catheterization difficult to perform, doppler echocardiography is frequently used for screening and diagnosing PH. The MCTD Research Committee set the revised criteria for MCTD-PH, in which the threshold of estimated pulmonary arterial systolic pressure value for diagnosis of pulmonary arterial hypertension (PAH) is set at 36 mmHg, as proposed by the European Society of Cardiology. Right heart catheterization is strongly recommended for commencing the treatment. Since PH due to thromboembolism can potentially be cured surgically, lung perfusion scintigraphy should be performed for all patients diagnosed with PH. Most CTD-PH are PAH, and since idiopathic PAH (IPAH) patients sometimes have immune disorders, treatment for IPAH may be applicable to CTD-PH. The greatest difference between the treatment strategy for CTD-PH and IPAH is the usage of corticosteroids and other immunosuppressants. The MCTD Research Committee updated its therapeutic guidelines for MCTD-PH in 2011. Validation of these guidelines is also needed.

Efficacy, safety, and pharmacokinetics of ambrisentan in Japanese adults with pulmonary arterial hypertension.

OBJECTIVE: To investigate the efficacy, safety, and pharmacokinetics of ambrisentan in Japanese adults with pulmonary arterial hypertension (PAH). RESEARCH DESIGN AND METHODS: In this open-label, uncontrolled, dose-escalation study, 25 Japanese patients with PAH were scheduled to receive 5 mg of ambrisentan once daily for the first 12 weeks, and 10 mg once daily for an additional 12 weeks. The primary endpoint was improvement in exercise capacity from baseline which was indicated by 6-minute walk distance; the secondary endpoints included World Health Organization functional class, Borg dyspnea index, plasma brain natriuretic peptide level, and cardiopulmonary hemodynamics. CLINICAL TRIAL REGISTRATION: NCT00540436. RESULTS: At week 24, improvements were noted in all endpoints, with no clinically significant elevation of serum aminotransferase level. Pharmacokinetics in these Japanese patients was similar to that of non-Japanese populations, suggesting that once-daily dosing is appropriate in Japanese patients. Ambrisentan was generally well tolerated. No new safety signals were identified. LIMITATION: This study lacked a control group and was insufficiently powered to reach definitive conclusions on the efficacy of ambrisentan. CONCLUSION: Ambrisentan is considered as safe and effective for Japanese adults with PAH.

A morphological study of the blood vessels associated with periodontal probing depth in human gingival tissue.

Gingival tissues in human cadavers were examined the blood vessel diameter in the depths of the gingival pockets such as three groups: gingiva adjacent to a sulcus of 2 mm (Group 1); gingiva adjacent to a 2-4-mm sulcus (Group 2); and gingiva adjacent to a sulcus of > 4 mm (Group 3). A meaningful significant difference was seen observed in gingival pocket side, intermediate and outer layer side regions of the gingiva. A meaningful significant difference was seen found in intermediate part and the outer layer of the gingiva in Group 3. Other gingival biopsies were performed on a human body donation specimen to examine CD-31 positive endothelial cells of blood vessels by an immnohistochemical method. Our results suggest that the periodontal probing depth reflect the blood vessel organization of human gingival tissue.

Observing the bony canal structure of the human maxillary sinus in Japanese cadavers using cone beam CT.

We observed the location of the posterior superior alveolar artery (PSAA) and nerve at the macroscopic level between the maxillary sinus (MS) and surrounding bone of the anterior region of the maxilla. This study was completed using cone beam computed tomography (CBCT) imaging of 19 human cadavers with 38 sides of Japanese origin (ranging in age from 59-94 years, mean 77.7 +/- 9.8 years) that were prepared for this study. The bony canal structure of the inner surface of the maxilla was clearly apparent in our results, and the bony canals were classified into three types according to the structure along the course of the PSAA: canal-like, ditch-shaped tunnel and fragmented, and the lest sides were undefined. Calcitonin gene-related peptide (CGRP)-positive fibers were identified along the PSAA in the bony canal of the maxilla by immunohistochemistry. The presence of the bony structure and CGRP-positive nerve fibers along the PSAA suggests that there is risk to the PSAA during surgery involving graft implant in the floor of the maxillary sinus.