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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.

The efficacy of biologics in treating adult Still’s disease (ASD) is suggested, but the information is still lacking and the validation is insufficient. To determine the efficacy of several biologic agents in refractory ASD in Japan, a multicenter survey was performed. Clinical data on 16 ASD patients who had been treated with at least 1 of the biological agents (total 24 occasions) were collected retrospectively. Infliximab was used in 9 cases, etanercept in 4, and tocilizumab in 11. Half of the patients that had been treated initially with infliximab or etanercept were changed to another biologics. Tocilizumab was effective in cases switched from another 2 drugs. Tocilizumab showed efficacy in treating both systemic and arthritic symptoms and showed apparent steroid-sparing effect and the highest continuation rate. Tocilizumab may be a promising biologic agent in refractory ASD.

Objective Interferon regulatory factor 5 (IRF-5) is a transcription factor that mediates intracellular signals activated by engagement of Toll-like receptors (TLRs). IRF5 polymorphisms are associated with an increased or decreased risk of systemic lupus erythematosus (SLE) in various human populations, but the precise role of IRF5 in SLE development is not fully understood. This study was undertaken to examine the role of IRF5 in the development of murine lupus. Methods We crossed gene-targeted IRF5-deficient (IRF5−/−) mice with MRL/MpJ-lpr/lpr (MRL/lpr) mice and examined the progeny for survival, glomerulonephritis, autoantibody levels, immune system cell populations, and dendritic cell function. Results IRF5−/−MRL/lpr mice survived longer than control IRF5+/+MRL/lpr mice and displayed only very mild glomerulonephritis. Autoantibodies to SLE-related nuclear antigens were lower in IRF5−/−MRL/lpr mouse serum, and numbers of activated CD4+ T cells were reduced in the spleen. Splenic DCs from IRF5−/−MRL/lpr mice produced lower levels of inflammatory cytokines when treated in vitro with TLR-7 or TLR-9 ligands or immune complexes. Interferon-α production in response to CpG was also decreased. Conclusion Our results show that IRF5 is a crucial driver of lupus development in mice, and indicate that IRF5 may be an attractive new target for therapeutic intervention to control disease in SLE patients.

OBJECTIVE B cells lacking RP105 produce autoantibodies in patients with SLE. Expression of B-cell activating factor (BAFF) binding receptors (BBRs) and survival of RP105(-) B cells from SLE patients were examined. METHODS Detection of difference of gene expression between RP105(-) and RP105(+) B cells was done by DNA microarrays. Surface expression was confirmed by flow cytometry. The contribution of BAFF, a proliferation-inducing ligand (APRIL) and monomers/trimers of sCD40L to survival of RP105(-) and RP105(+) B cells was examined. RESULTS Gene expression of B-cell maturation antigen (BCMA) was different among BBRs in RP105(-) and RP105(+) B cells in SLE. Preferential expression of BCMA on RP105(-) B cells was confirmed compared with RP105(+) B cells by flow cytometry, although BAFF receptor (BAFF-R) expression on RP105(-) B cells was significantly lower. Additionally, relative ratios of BCMA/BAFF-R expression on RP105(-) B cells were increased significantly in SLE patients compared with normal subjects. Stimulation by sCD40L decreased the number of surviving RP105(-) and RP105(+) B cells in vitro. RP105(+) B cells were not rescued from sCD40L-induced cell death by BAFF and/or APRIL. In contrast, either BAFF or APRIL maintained the survival of RP105(-) B cells due to avoidance of cell death. Activated RP105(-) B cells reduced BAFF-R and increased BCMA levels. CONCLUSIONS RP105(-) B cells from SLE patients showed more preferential expression of BCMA compared with BAFF-R than normal subjects, and were possibly regulated by BAFF/APRIL. Our results provide a new insight of BCMA and their ligands in B cells from SLE patients.

A 67-year-old man clinically diagnosed a year earlier with sarcoidosis based on low-grade fever, lymphadenopathy, trunk skin rash, and histopathological skin tests was admitted for newly developing subcutaneous nodules on the trunk and arms and fever of 38 degrees C. Although initially suspected of recurrent sarcoidosis, he was diagnosed with Mycobacterium chromogenicum infection isolated from skin lesion culture. Combined clarithromycin of 800 mg/day, ethambutol of 750 mg/day, and embiomycin of 0.5 g/day was started, after which fever declined and WBC count and CRP decreased to normal in a week. One month later, skin lesions had disappeared. This case is interesting considering the association of nontuberculous mycobacterial infection with sarcoidosis.

With the revision of the Good Clinical Practice (GCP) in 1997, the Clinical Trial Center was established at Saga University Hospital in 1999, where clinical research coordinators (CRC) of nurses and pharmacists have been carrying out support for clinical trials since June 2000. At present, two pharmacists, two nurses, and three clerical work assistants support the execution of clinical trials; however, in recent years the number of clinical trial commissions has been gradually decreasing. On this occasion, in order to carry out even higher quality and smoother clinical trials, we conducted a questionnaire targeting the sponsors of clinical trials (head monitors) to evaluate this hospital's system for the execution of clinical trials from the sponsor's standpoint. Moreover, for the purpose of comparison with the systems of other institutions, the same questionnaire was conducted on two other hospitals-the University of Occupational and Environmental Health, Japan and the Social Insurance Shimonoseki Kousei Hospital. The problems of the clinical trial execution in our team turned out lack of knowledge concerning GCP and our complex system from the result of the questionnaire.

For over 10 years there have been no clinical studies about adult-onset Still’s disease (AOSD) in Japan. We aimed to investigate recent clinical features and treatment of AOSD and to evaluate the efficacy of cyclosporin A (CyA) in the treatment of AOSD. The data from 34 patients with AOSD who were admitted to our hospital between 1994 and 2007 were analyzed retrospectively. Of several immunosuppressive agents, the efficacy of CyA given to seven patients was precisely evaluated. Clinical features observed in this study did not differ from those in our previous study, and serum ferritin levels were elevated in all the patients. Among immunosuppressive agents CyA, used concomitantly with corticosteroids (CS) for seven patients with severe AOSD, proved to be very effective. The disease was led to remission promptly by CyA in six patients, and all the patients except one experienced no recurrence. These results suggest that CyA can be one of the potent candidates to be used next to CS for patients with AOSD that is resistant to CS.

To assess the effects of disease activity of systemic lupus erythematosus (SLE) and high-dose corticosteroids on endothelial injuries, the significance of soluble endothelial cell protein C receptor (sEPCR) and soluble thrombomodulin (sTM) was analyzed. Serum levels of sEPCR and sTM were measured by enzyme-linked immunosorbent assay (ELISA) cross-sectionally in 97 SLE patients, 49 patients with other rheumatic diseases and 22 normal subjects. The changes in these levels upon corticosteroid treatment were also analyzed in 41 patients. The levels of sEPCR and sTM were both higher in SLE and other rheumatic disease patients than in normal subjects. When low-dose corticosteroids were used, both the level of sEPCR and the ratio of positive tests for sEPCR were significantly higher in active SLE patients than in inactive patients [median 2.30 ng/ml (range 0.00–147.10 ng/ml) vs 0.00 ng/ml (0.00–58.90 ng/ml) and 53.5 vs 13.0%, respectively] (P < 0.005). Moreover, the ratio of positive tests for sEPCR was higher after corticosteroid treatment in 9 of 19 (47.3%) SLE patients compared to other rheumatic diseases (3/22; 13.6%). Although the mean level of sTM was significantly higher in active SLE patients than in inactive patients, the ratio of positive tests for sTM was not affected by disease activity or corticosteroids. In conclusion, the positive test for sEPCR is a more sensitive biomarker than that for sTM in reflecting endothelial injuries caused by active disease and often by corticosteroids in SLE.

Objective. Accumulating evidence suggests that B-cell depletion therapy by rituximab may be effective for autoimmune disorders. However, an optimal dose of rituximab and a mechanism of its action remain to be established. We performed a dose-escalation study for treatment of Japanese patients with autoimmune diseases including eight with SLE and one with Evans’ syndrome. Methods. Rituximab was infused intravenously, weekly 4 times in a dose-escalating fashion at three different doses of 100, 250 or 375 mg/m 2 to three patients each. Immunological parameters were monitored at certain points until 12 months after the treatment. Results. Rituximab was well tolerated and safe in these patients. Seven out of eight SLE patients and one with Evans’ syndrome clinically responded completely or partially to the treatment. Four patients achieved long-term remission (18–30 months) without any additional treatment. In these patients, a significant decrease in circulating B cells continued for 6 months after the treatment. The mean fluorescence intensities of CD19, CD21, CD40 and BR3 on the residual B cells as well as the percentage of CD69þ CD4þ T cells decreased significantly. Serum TNF-� levels decreased significantly on day 2. The Th1/Th2 balance of CD4þ T cells gradually shifted towards a Th1 type by 6 months. Conclusion. In addition to B-cell depletion, modification of B-cell and T-cell phenotypes as well as cytokine profiles may be involved in the action of rituximab.

Objective This study aimed to evaluate the possible effects of Helicobacter pylori (H. pylori) infection in reflux esophagitis with scleroderma. Patients and Methods There were a total of 138 patients with scleroderma in our hospital between October 1998 and June 2005. Among these patients, 64 consecutive patients of scleroderma, who did not receive medication for gastrointestinal diseases, underwent endoscopy after informed consent. H. pylori was examined using an H. pylori IgG ELISA. The endoscopists graded esophageal mucosal breaks according to the Los Angeles Classification of Esophagitis. Results Among the 64 patients, 37 patients (57.8%) were positive for H. pylori infection. Reflux esophagitis was observed in 10 of 37 H. pylori-positive patients and in 19 of 27 H. pylori-negative patients. Significantly fewer H. pylori-infected patients had reflux esophagitis than H. pylori-negative patients (p

Inducible costimulator (ICOS) is a costimulatory molecule expressed in activated T cells and plays an important role in T-cell-dependent immune responses. We investigated the role of ICOS in the development of autoimmune diseases in MRL/Mpj-lpr/lpr (MRL/lpr) mice. ICOS was expressed on CD4+ T cells from adult MRL/lpr mice. ICOS-deficient MRL/lpr mice showed mild lymphoadenopathy and a decreased memory type CD4+ T cells in the spleen. The anti-dsDNA antibody levels were decreased. CD4+ T cells from ICOS-deficient MRL/lpr mice showed less of a bias to Th1 and an enhanced production of IL-4 in response to anti-CD3 antibody in comparison to those from wild-type MRL/lpr mice. Although ICOS-deficiency abrogated renal vasculitis completely, the severity of glomerulonephritis was not altered. ICOS is considered to play a role in CD4+ T cell activation, autoantibody production, and renal vasculitis. However, it is not essentially required in the development of glomerulonephritis.

Although osteonecrosis of femoral head (ONF) is one of the serious complications in systemic lupus erythematosus (SLE) associated with corticosteroid therapy, there has been few trials of prevention of ONF described. We aimed to prevent ONF in steroid-treated SLE patients using anticoagulant, warfarin, conducting a multicenter prospective study. Sixty newly diagnosed SLE patients requiring 40 mg/day or more prednisolone were alternately assigned to either of two groups; a warfarin group and a control one. Warfarin (1 ∼ 5 mg/day) was started together with the beginning of steroid therapy and continued at least for three months. Patients were observed for the development of silent ONF by magnetic resonance imaging (MRI) and symptomatic ONF by plain radiography for over five years. The warfarin group consisted of 31 patients (62 hips) and the control one 29 patients (58 hips). Silent ONF developed in 13 hips (21%) and 19 hips (33%) in the warfarin group and the control group, respectively ( P = 0.13). On the other hand, warfarin tended to prevent symptomatic ONF; only three hips of 62 (4.8%) in the warfarin group and eight hips of 58 (14%) in the control group ( P = 0.08) developed silent ONF. It was also found that silent ONF developed, if it did, very early; within three months in 16 of 18 patients (89%). Among risk factors for silent ONF, steroid pulse therapy was most outstanding and it seemed to overcome the effect of warfarin. Taken together, for the time being, anticoagulant therapy, if not significantly sufficient, may be of use for the prevention of steroid-induced ONF in SLE. We consider that this study added to important evidence for the pathogenesis and prevention of ONF.

A 50-year-old woman reporting sudden-onset chest pain was diagnosed as having pulmonary infarction associated with Takayasus arteritis. She had experienced moderate malaise and cough for 3 months. Computed tomography (CT) and magnetic resonance imaging (MRI) showed wedge-shaped infiltrative shadows typical of pulmonary infarction in the right lung. Although pulmonary artery involvement in Takayasus arteritis is well documented, most patients show only signs of mild to moderate pulmonary hypertension. Few reports discuss patients with symptoms due to pulmonary infarction as the initial manifestation. Takayasus arteritis should therefore be considered a differential diagnosis in pulmonary infarction.

Microscopic polyangiitis (MPA) is a rare systemic vasculitis syndrome, which is often accompanied by positive myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA). While pulmonary involvement of MPA consists mainly of diffuse alveolar hemorrhage and interstitial pneumonia, bronchiectasis has been reported as a pulmonary lesion in association with MPA. To investigate the clinical features of patients with MPA, focusing on the presence or the absence of preceding chronic airway diseases (CAD), we conducted a retrospective observational study of 26 patients in the last 13 years at Saga University Hospital. The clinical records and radiologic chest examinations were reviewed retrospectively. Pulmonary manifestations were alveolar hemorrhage in 3 patients (12%) and interstitial pneumonia in 5 (19%). Bronchiectasis, defined by the findings of chest radiograph and computed tomography, was found in 9 patients (35%). Four patients (15%) with bronchiectasis and one patient (4%) with chronic bronchitis had experienced chronic bronchial suppuration prior to the onset of MPA. Ten patients were classified as having chronic airway disease (CAD) before the onset of MPA. MPO-ANCA tended to be lower in the CAD group than in the non-CAD group. None of the patients in the CAD group had pulmonary hemorrhage or interstitial pneumonia. Only one patient (10%) in the CAD group died within 90 days of the onset of MPA, while 7 (43.8%) of the non-CAD group died. Our study suggests that MPA may result in part from CAD and that the clinical course of MPA with CAD may be different from MPA without CAD.

Objectives To investigate the relationship between the production of Th1/Th2 cytokines and cell kinetics, cell division and proliferation in patients with Behcet's disease (BD). Methods Peripheral venous blood was drawn from patients with BD (n = 24; 10 patients with active and 14 patients with inactive BD) and normal subjects (n = 22). Peripheral blood mononuclear cells were separated immediately and were cultured with concanavalin A (Con A) followed by phorbol 12-myristate 13-acetate and ionomycin (PMA+Ion). Intracellular cytokine production of interferon-gamma (IFN-gamma) (Th1) and IL-4 (Th2) in CD4(+) T cells was determined by flow cytometry. Furthermore, CD4(+) T cells labelled with CFSE [5 (and 6) carboxyfluorescein diacretate, succinimidyl ester] were stimulated and the cells were analysed for entry into the cytokine production effector pathway during cell division in active BD and normal subjects. Results In active BD, enhanced entry into the Th1 response effector pathway of CD4(+) T cells was observed after stimulation with Con A followed by PMA+Ion. Analysis of CD4(+) T cells at an identical cell division number in response to Con A followed by PMA+Ion revealed that IFN-gamma-producing cells were increased in active BD patients compared with normal subjects. These results suggest that the Th1 response of dividing CD4(+) T cells is predominantly operating in active BD. Dividing CD4(+) T cells stimulated with Con A followed by PMA+Ion showed a phenotype of activated effector memory T cells (CD45RA(low), CD45RO(+), CD69(high)). Conclusions Cell kinetics play a crucial role in Th1 cell differentiation and pathophysiology in BD.

Tob is a member of the Tob/BTG family, a novel class of anti-proliferative proteins. To investigate the involvement of tob as a tumor suppressor gene in human lung cancer, we analyzed the expression of tob mRNA and protein in lung cancer tissue and adjacent normal lung tissue. Immunohistochemical analysis using anti-Tob antibody showed decreased expression of Tob in 72% (31/43) of lung cancer tissues. Furthermore, 95% (19/20) of squamous cell carcinoma patients showed an apparent decrease in Tob in cancer tissues, associated with smoking status. The phosphorylated form of Tob, an inactive form of Tob, was detected in 76% (16/21) of cancer tissues of adenocarcinoma patients, but not in normal alveolar epithelial cells. Either a decrease in Tob expression or an accumulation of phosphorylated Tob was observed from early clinical stages, even in bronchial dysplasia, a premalignant lesion of squamous cell carcinoma. The above findings suggest that the disruption of anti-proliferative Tob plays a distinct part in the early stage of lung carcinogenesis.

Objective: To determine the prevalence of retinal disease in systemic sclerosis (SSc) and to characterise the findings of retinopathy. Additionally, to analyse the association of retinal disease with other clinical/laboratory findings, particularly the findings of nailfold capillaries in patients with SSc. Methods: Photographs of the ocular fundi were taken and were evaluated by an ophthalmologist who was unaware of the SSc status of the patients. The nailfold capillaries were analysed with a dermatoscope. Patients were divided into two groups according to the presence (group A) or absence (group B) of retinal disease. Results: Retinal findings of the patients with SSc consisted of hard exudates, vascular tortuosity, microhaemorrhage, and macular degeneration. The prevalence of retinal disease among the patients with SSc was 34% (10/29), compared with 8%(3/38) among the controls (p=0.011). The mean systolic blood pressure and the age of the patients in group A were significantly higher than those in group B. However, there was no significant difference in the nailfold capillary damage between groups A and B. Conclusion: Retinal abnormalities are often seen in patients with SSc and they may reflect the vascular changes characteristic of SSc. However, retinal changes may differ in quality from the changes of nailfold capillaries.

A 20-year-old male was admitted to our hospital with the chief complaints of high fever and pain around his right hip joint. He had his right knee injured with a slight abrasion three weeks before. The diagnosis of suppurative lymphadenitis of inguen was made, and intravenous cefotiam was started. Despite these treatments his fever continued, general edema and dry cough appeared. Arterial blood gas showed severe hypoxia and chest X ray revealed marked cardiomegaly associated with ground-glass opacity over bilateral lower pulmonary fields. Slight renal insufficiency was also observed. On the fifth hospital day, the culture specimens of both blood and pus from the abrasion on admission yielded Streptococcus pyogenes. His condition was diagnosed as severe group A Streptococcus infection, then antibiotics were switched to intravenous administration of high dose aminobenzyl penicillin and clindamycin in combination with protease inhibitor, urinastatin. After these treatments, his condition improved and he was discharged from the hospital after one month. Group A Streptococcus may cause uncommon but life-threatening infection such as septicemia. Early recognition of the disease and prompt initiation of appropriate treatment may lead to successful outcome.

We report an elderly case of adult-onset Still’s disease (AOSD) with atypical presentation. The patient, an 80-year-old female, visited our hospital due to itchy linear urtical rash with low grade fever which occurred after taking a significant amount of blowfish milt four days before. Oral prednisolone of 30mg/day was successful. However, remittent fever appeared after reducing the prednisolone dose accompanied by the similar skin lesion. Hyperferritinemia was evident on the admission and the diagnosis of AOSD was made. We should keep in mind the presence of AOSD with atypical presentation in elderly patients.

BACKGROUND—It has previously been shown that RP105, a new B cell surface protein, is lost in activated human B cells. OBJECTIVE—To investigate whether there is a difference in B cell activation between patients with dermatomyositis (DM) and those with polymyositis (PM) using RP105 as a marker. METHODS—The population of RP105 negative B cells (activated B cells) in the peripheral blood mononuclear cells of seven patients with dermatomyositis (DM) and 11 with polymyositis (PM) was analysed by flow cytometry. RESULTS—The percentage of RP105 negative B cells in the peripheral blood of patients with PM was low (5.8 (SD 2.4)%), similar to that of normal subjects. In contrast, all patients with DM showed increased RP105 negative B cell populations (33.0 (6.9)%). Bronchoalveolar lavage fluid from a patient with DM and active interstitial pneumonitis contained a large number of RP105 negative B cells. CONCLUSION—These findings suggest that the expansion of RP105 negative B cells is a hallmark of DM, and that B cell activation in DM may be pathogenetically different from that in PM.

TNF is a potent proinflammatory cytokine important for the development of arthritis in human and animals. We have investigated the roles of TNF receptor-1 (TNFR1) and TNF receptor-2 (TNFR2) in collagen-induced arthritis (CIA) by inducing CIA in mice genetically deficient in TNFR1. TNFR1-/- mice developed arthritis with similar incidence and severity as TNFR1+/- littermates, indicating that TNFR1 is redundant for the development of CIA. Anti-type II collagen (CII) antibody levels and T cell responses to CII did not differ between TNFR1-/- mice and controls. Neutralization of TNF with soluble TNF binding protein suppressed the development of arthritis in TNFR1+/- mice but not in TNFR1-/- mice, indicating that TNFR2 cannot substitute for TNFR1 for the proinflammatory function. To further investigate the functions of TNFR2, TNFR1-/- mice were injected with murine TNF-alpha at different stages during the course of CIA. Repeated TNF-alpha injection during the early induction phase enhanced the development of arthritis, but inhibited arthritis when administered during the late progression phase. These results show that the engagement of TNFR2 by TNF is involved in the development of CIA in the absence of TNFR1 and that opposing signals can be transduced by TNFR2.

A 57-year-old man presented with pneumonia, respiratory distress, and myelodysplastic syndrome. A diagnosis of Legionnaires' disease due to Legionella pneumophila (L. pneumophila) was established. The patient had long been drinking tap water via a conduit from a hot spring resource, from which L. pneumophila was also isolated. Both the patient's strain and the water strain of L. pneumophila were identified as serogroup 1, and the genetic relatedness between the two strains as seen by pulsed-field gel electrophoresis was 87%. The patient was successfully treated with erythromycin, fluoroquinolone, and rifampicin. This case raises an important issue on public health represented by legionellosis in Japan.(Internal Medicine 40:1064-1067, 2001)

The relation between HLA class II alleles and clinical findings were examined in Japanese patients with systemic lupus erythematosus (SLE). In 284 patients with multicenter SLE, HLA class II alleles were examined using the DNA typing method, and the results were compared with the clinical findings. The frequency of DRB1*0101 and DQB1*0501 significantly increased in male patients, and that of DRB1*0803 significantly increased in patients over 50 years of age. In relation to cutaneous manifestations, there were positive photosensitivity associations with DQA1*0101 and/or DQA1*0301, malar rash with DQA1*0101 and/or DRB1*0901, alopecia with DQA1*0101, skin ulcers with DRB1*0401, and oral ulcers with DQA1*0301. In addition, there were also positive associations of myalgia with DRB1*1406 and negative associations of aseptic bone necrosis with DQA1*0601, and hepatomegaly with DRB1*0405 and/or DQA1*0401. In relation to laboratory findings, there were positive associations of hemolytic anemia with DRB1*1402 and negative associations of leukopenia with DQA1*0601, lymphopenia with DQA1*0301, and proteinuria with DRB1*0901. Interestingly, DQA1*0101 and/or DQB1*0501 were significantly associated with WHO classification type II rather than type IV. In patients with SLE, some HLA types related to clinical or laboratory findings.

Objective To investigate how patients with bacteremic sepsis are managed in a tertiary care teaching hospital. Patients and Methods Prospective observational study on patients with bacteremic sepsis. Clinical and microbio-logical characteristics of bacteremic sepsis were analyzed in relation to prognosis. Severity of the illness was quantitatively analyzed by the APACHE (Acute Physiology, Age, Chronic Health Evaluation) III scoring system. Also investigated was how closely physicians paid attention to acute physiological alterations in patients. Results The 28-day mortalities in fifty hemodynamically stable patients and in twenty-three septic shock patients were 26% and 52%, respectively (p=0.028). Gram-positive organisms accounted for 54% of all organisms, with the mortality and incidence of septic shock being the same as with Gram-negative infections. The mean APACHE III score was 42.9 in survivors, and 76.5 in non-survivors (p < 0.001). Although serum levels of C-reactive protein and acute physiology score (APS) was significantly higher in non-survivors than in survivors, the correlation with APACHE III score was more prominent in APS. The number of vital signs recorded was 1.67 in physicians and 3.6 in nurses (p < 0.001). Conclusions The present study proved that the APACHE HI score accurately discriminates between survivors and non-survivors of patients with sepsis. By addressing the need for an objective evaluation of severity of illness, it strongly recommends that physicians should be made aware of physiologically defined sepsis and that they should pay closer attention to patients' physiological alterations to identify the development of sepsis in critically ill patients.(Internal Medicine 39: 901-909, 2000)

MRL/Mpj-lpr/lpr (MRL/lpr) mice develop autoimmune disorders, including lymphoproliferation, glomerulonephritis, autoantibody production, and hypergammaglobulinemia. To investigate the role of the costimulatory molecule CD28 in the development of these disorders, MRL/lpr mice lacking CD28 were generated by gene targeting. Compared with CD28+/+ MRL/lpr mice, CD28−/− MRL/lpr mice showed decreased lymphadenopathy but increased splenomegaly associated with the expansion of abnormal B220+ TCRαβ+ T cells. Although levels of IgM Abs were unchanged in CD28−/− MRL/lpr mice, the production of anti-DNA IgG Abs and IgG rheumatoid factors were suppressed. IgG deposition in the glomeruli was markedly decreased, and the development of glomerulonephritis was significantly retarded. Furthermore, renal vasculitis and arthritis were absent in CD28−/− MRL/lpr mice. These results indicate that, although CD28 is not required for the generation of the abnormal T cell population in MRL/lpr mice, it does play an important role in the development of autoimmune disease in these animals.

Fas is a cell surface receptor that controls a signal transduction pathway leading to apoptosis. We established an antihuman Fas monoclonal antibody (mAb)-resistant variant, kit-225-FR, from the human T cell line, kit-225. Flow cytometric analysis revealed that the expression of Fas molecules on kit-225-FR was preserved. The defect in Fas molecule was not detected either by reverse transcription polymerase chain reaction (PCR) analysis of the Fas transcript or by PCR-single strand conformation polymorphism analysis of the Fas gene in kit-225-FR. Although kit-225-FR was resistant to a high concentration of anti-Fas mAb, apoptosis could be induced, as with the wild type, by exogenous C2-ceramide exposure. MORT1/FADD was expressed at wild-type level in kit-225-FR, as determined by Western blot analysis. It therefore appears that the apoptotic signal transduction in kit-225-FR is defective between FADD and the sphingomyelin-ceramide pathway. By comparing the differences from the wild-type kit-225, kit-225-FR would serve as a useful cell line for analyzing Fas-specific signal transduction pathways in detail.

Polyangiitis overlap syndrome is a new disease entity and the reported cases in the literature are still limited. We describe a female patient presenting with finger ulcers, skin eruptions, pleural effusion, interstitial pneumonia and eosinophilia. Skin biopsy showed systemic small-sized angiitis and thrombosis. She was diagnosed as having polyangiitis overlap syndrome and was successfully then treated with corticosteroid. It is also of interest that the disease activity was correlated with the number of eosinophils in peripheral blood. The measurement of the serum level of major basic protein released from eosinophils functioning as a coagulant indicated the possible association of eosinophilia with thrombosis and polyangiitis.

Deficiency of the α-γ subunit of the eighth component of complement (C8α-γD) is frequently associated with recurrent neisserial infections, especially meningitis caused by Neisseria meningitidis. We here report the molecular basis of C8α-γD in two unrelated Japanese subjects. Screening all 11 exons of the C8α gene and all 7 exons of the C8γ gene and their boundaries by exon-specific PCR/single-strand conformation polymorphism demonstrated aberrant single-stranded DNA fragments in exon 2 of C8α gene in case 1 and in exons 2 and 9 of C8α gene in case 2. Nucleotide sequencing of the amplified DNA fragments in case 1 revealed a homozygous single-point mutation at the second exon-intron boundary, inactivating the universally conserved 5′ splice site consensus sequence of the second intron (IVS2+1G→T). Case 2 was a compound heterozygote for the splice junction mutation, IVS2+1G→T, and a nonsense mutation at Arg394 (R394X). R394X was caused by a C to T transition at nucleotide 1407, the first nucleotide of the codon CGA for Arg394, leading to a stop codon TGA. No mutations were detected in the C8γ gene by our method. Our results indicate that the pathogenesis of C8α-γD might be caused by heterogeneous molecular defects in the C8α gene.

We conducted a case-control study to evaluate the contribution of some risk factors to the development of scleroderma. Fifty-seven patients with scleroderma (seven males and 50 females) were interviewed with a structured questionnaire at Saga Medical School Hospital from 1993 to 1995. Fifty-seven controls, who were individually sex and age matched with each case, were also interviewed with the same questionnaire during the same period. Eight individuals of parents or siblings of the scleroderma patients had Raynaud’s phenomenon, as compared to none of the controls (P

An elevated immunoglobulin (Ig)M concentration in serum is a common and distinctive feature of primary biliary cirrhosis (PBC). Little is known, however, about the mechanism of hyper-IgM in PBC. CD40 ligand (CD40L) has a crucial role in immunoglobulin class switching in B cells. Mutations in the gene encoding CD40L are known to induce X-linked hyper-IgM syndrome. To identify mutations in the gene for CD40L in PBC patients, we analyzed CD40L gene mutations, using reverse transcription (RT)-PCR single-strand conformation polymorphism (SSCP) analysis. No mutations were detected in cDNA from any of 24 PBC patients by the RT-PCR-SSCP technique. These data suggest that other, unidentified mechanisms are involved in hyper-IgM in PBC patients.

We report a rare case of a patient with Behçet’s syndrome who developed end-stage renal failure due to crescentic glomerulonephritis (GN). A 20-year-old male patient had suffered from uveitis, aphthous mouth ulcers and genital ulceration for the past 7 years. His renal function rapidly deteriorated and renal biopsy specimens obtained when his serum creatinine level was 3 mg/dl showed diffuse proliferative GN with fibrous crescent formation in 75% of glomeruli excluding totally sclerotic glomeruli. Immune complexes were identified by demonstration of complement and immunoglobulins in the glomeruli. He developed end-stage renal failure during a 1-year course and received maintenance hemodialysis. We reviewed the literature on severe forms of GN in patients with Behçet’s syndrome.

経過中,大腸の肉芽腫性壊死性血管炎によると思われる横行結腸穿孔をきたし,その後も治療抵抗性に大腸潰瘍が遷延しているウエゲナー肉芽腫症(WG)の1例を経験した.症例は58歳女性.著明な咽頭潰瘍を主訴に1994年12月当院に入院し,抗生物質抵抗性の肺浸潤影,腎障害, C-ANCA陽性などからWGと診断した.ステロイドパルス後,横行結腸穿孔をきたし,緊急開腹にて腸管・腸間膜の血管炎様肉眼所見を認めた.人工肛門を造設し,局所安静とステロイド+シクロフォスファミドで加療し咽頭・肺・腎所見は軽快したが,壊死性肉芽腫性血管炎に伴う大腸潰瘍が術後10カ月以上遷延している.統計上,消化管病変は, WGの初発および経過中の症状としてはほとんどみられないが,死因の約12%を占めており,治療ならびに経過観察においては充分注意する必要があると考えられた.

Production of the third and fourth components of complement (C3, C4) by smooth muscle cells was investigated by using normal human aortic smooth muscle cells (AoSMC), human smooth muscle cell line (G402) and vascular smooth muscle cells obtained from human umbilical cord vein (UVSMC). AoSMC spontaneously produced both C3 and C4 at 15 ng/10(6) cells/72 hr and 22 ng/10(6) cells/72 hr, respectively, and both were enhanced by interferon-gamma (IFN-gamma). Although phorbol 12-myristate 13-acetate (PMA) and tumour necrosis factor-alpha (TNF-alpha) enhanced C3 production, C4 production was reduced by these agents. On the other hand, G402 produced C4 but not C3 in a dose-dependent manner when cultured with IFN-gamma. UVSMC produced only a small amount of C3 and C4 compared with AoSMC or G402. C3 and C4 produced by AoSMC were confirmed to be identical with their human serum counterparts as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and measurement of haemolytic activity. Northern blotting analysis showed that the expression of mRNA of C3 and C4 was enhanced by TNF-alpha and IFN-gamma, respectively, in AoSMC. Our findings suggest the importance of smooth muscle cells as a source of components of complement in vascular diseases including vasculitis.

A 65-year old man presented with complaints of sclerosis of skin and numbness in the extremities. During last 10 year, he had developed monoclonal gammopathy, Raynaud's phenomenon, ischemic heart disease, sigmoid colon cancer, hyperkalemia, polyneuropathy and scleroderma-like skin changes. Laboratory examinations revealed a monoclonal protein (IgA-lambda) and an elevated serum level of IL-6. Subsequently a diagnosis of POEMS syndrome was made based on the clinical features and laboratory findings which were characteristic of this syndrome. Further examinations showed the presence of glomerulonephritis and brain tumor. These various complications are of great interest in understanding the pathogenesis of POEMS syndrome.

We investigated the effect of beraprost sodium (BPS) on the Raynaud's phenomenon on 15 patients with systemic sclerosis, 3 with mixed connective tissue disease and 1 with Raynaud's disease, respectively. After 12 weeks of administration of 60 micrograms/d BPS, the duration and the incidence of the Raynaud's symptom were significantly reduced and the dermal temperature on the fingers was found to be elevated. Of the parameters which are known to reflect vascular endothelial damages such as tissue plasminogen activator (t-PA), von Willebrand's factor (vWF) and endothelin, the plasma level of t-PA was significantly reduced by BPS. Furthermore, the capillary loop in the nail bed of the fingers seemed to increase in one patient by the treatment with BPS. These results suggest that BPS has a capacity to repair peripheral vascular damages resulting in the improvement of Raynaud's phenomenon.

We report a case of Takayasu arteritis. A woman, 24 years old, was admitted because of fever of unknown etiology. Infection was ruled out. Bruit and asymmetrical pulsation were not found. Ga-scintigram showed abnormal uptake in her upper abdomen. Abdominal echogram revealed neither evidence of abscess nor lymphadenopathy. On abdominal computed tomography, a wall thickening of the abdominal aorta was revealed. In addition, abdominal magnetic resonance imaging(MRI) showed a wall thickening and an enhanced image by gadrinium enhancement. Although we could not carry out conventional aortography because of an allergy to lidocaine, she was diagnosed as having Takayasu arteritis. In response to steroid therapy, the fever promptly dropped and the data indicating inflammation were improved. On the MRI examination after 40 days of steroid therapy, the wall thickening of the abdominal aorta was found to be less prominent. We conclude magnetic resonance imaging is useful for diagnosis and follow-up of early and acute stage of Takayasu arteritis.

MCTDはRaynaud症状と手指腫脹を基本症状としてPSS, SLE, PM/DMの症状を異なった比重で合わせもつため,治療は画一的には行なえない.治療方針の決定には病型に分類をすることが便利である.多くの場合ステロイド薬を使用するが,投与量は病型によって異なる.予後の悪い進行性の肺高血圧には大量のステロイド薬と抗凝固薬などを用いる.フォローする上では病型の変化に注意することと,肺高血圧の管理が重要である.

The fourth component of complement (C4) in urine was measured in 19 patients with systemic lupus erythematosus (SLE). Urinary C4 was detectable in all SLE patients using an enzyme linked immunosorbent assay. In 11 of 13 patients whose urinary C4 was serially measured, a decrease of urinary C4 was found in parallel with a decrease of disease activity of SLE. In the remaining 2 patients, the amount of C4 increased preceding a flare-up of the disease. The measurement of urinary C4 may be useful in evaluating the disease activity of SLE in individual patients and sometimes in predicting the flare-up of the disease. The specific hemolytic activity of excreted C4 and Western blotting analysis showed that urinary C4 consisted mainly of degraded fragments of C4. In two cases, camostat, a serine protease inhibitor, rapidly decreased the urinary C4 excretion, suggesting that the complement activation occurred in the glomerulus in lupus nephritis.

This study aimed to investigate phenotype of RP105(−) B cell subsets in patients with systemic lupus erythematosus (SLE). Flow cytometry was used for phenotyping RP105-negaive B cell subsets. Based on CD19, RP105, and CD138 expression, RP105(−) B cells consist of at least 5 subsets of late B cells, including CD19(+)RP105(int), CD19(+) RP105(−), CD19(low) RP105(−) CD138(−), CD19(low) RP105(−)CD138(int), and CD19(low) RP105(−) CD138(++) B cells. Especially, CD19(+)RP105(int) and CD19(low) RP105(−)CD138(int) B cells are significantly larger than other RP105(−) B cell subsets in SLE. By comparison of RP105(−) B cell subsets between patients with SLE and normal subjects, these subsets were detectable even in normal subjects, but the percentages of RP105(−) B cell subsets were significantly larger in SLE. The phenotypic analysis of RP105(−) B cell subsets suggests dysregulation of later B cell subsets in SLE and may provide new insights into understanding regulation of B cells in human SLE.

To find out when and how avascular necrosis of the femoral head (ANFH) develops in patients with SLE who are receiving corticosteroids, we carried out a 3-yr prospective study using imaging methods. Twenty-three patients with SLE who were free of hip pain and radiographically negative were enrolled in the study. Initially, abnormal findings characteristic of ANFH were detected in eight (35%) and six (26%) patients on MRI and radionuclide uptake bone scanning, respectively. During a 3-yr observation period abnormalities on MRI, bone scanning and radiography were found in four, five and four patients, respectively and three patients developed hip pain. Analyses of imaging changes demonstrated that only a small proportion of patients (2/8, 25%) who initially showed abnormal MRI progressed to be radiographically positive for ANFH over the 3 years. High doses of corticosteroids over the 3-yr period were to be responsible for the emergence of change in MRI abnormalities. It is also suggested that abnormal MRI findings tend to develop either within a relatively short interval after the start of corticosteroid treatment or are associated with the exacerbation of SLE.