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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.

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.

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.

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.

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)

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.

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.

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.

症例は, 36歳,女性.平成3年3月, 39°Cの発熱を主訴に近医に入院.全身性エリテマトーデス(SLE)と診断され同年4月よりprednisolone 60mg/dayの治療が開始されたがステロイド減量困難のため,平成3年10月7日当科に入院した.入院時hemophagocytic syndromeによる播種性血管内凝固症候群(DIC)の状態であったが呼吸器症状はなく,胸部X線像も正常であった. 10月9日より38°C以上の発熱が続き10月11日より咳嗽も出現するようになり,左肺上葉中心の大葉性肺炎が急速に進行したが, erythromycinが著効した.血清抗体価測定よりLegionella bozemanii肺炎と診断した.また尿中よりcytomegalovirus (CMV)を検出しganciclovirを使用したところ, hemophagocytosisおよびDICは改善した.本症例はCMV感染によるinfection-associated hemophagocytic syndromeを発症したSLEに,レジオネラ症でもまれなL. bozemanii肺炎を合併した1例で,免疫能低下の関与が示唆された.

We describe a case of vertebral osteomyelitis caused by Prevotella intermedia, which is an extremely unusual cause of vertebral osteomyelitis. The organism was isolated from vertebral biopsies and the patient was treated successfully with intravenous ampicillin-sulbactam and clindamycin. Diagnosis and management of this condition are described, and the importance of anaerobic bacteria in the pathogenesis of vertebral osteomyelitis is discussed.

We report a case of microscopic polyangiitis (mPA) and giant cell arteritis (GCA) (polyangiitis overlap syndrome) after influenza vaccination. A 67-year-old female with chronic kidney disease, who had been observed by a physician, presented fever and headache after immunization of influenza vaccine. She was diagnosed as having with mPA and GCA based on symptoms, worsening of renal function, biopsy of temporal artery (giant cell arteritis) and skin (microscopic polyangiitis), pulmonary involvement and the presence of myeloperoxidase-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA). She was treated with prednisolone (PSL) and the symptoms were improved. However, two months later she was presented with general physical weariness. She was diagnosed as having with pneumocystis pneumonia, cytomegalovirus infection and cryptococcosis. Despite intensive treatment, she was died and autopsy was performed. The present case suggests that the influenza vaccination may cause different types of vasculitis, mPA and GCA, through the common mechanism in pathophysiology. This patient is also the first case of mPA and GCA proven by histological examination.

There have been several reports indicating the association between recent stress experiences and the onset or the exacerbation of rheumatic diseases, although few such reports exist in patients with scleroderma (SSc). The present study was performed to elucidate whether there were any functional disturbances in the neuro-endocrine-immune system as a homeostatic system upon stress in SSc patients. Various serum levels of stress-related hormones and cytokines were examined before and after a mental calculation stress test, and a basal questionnaire study of sense of coherence (SOC, which is related to the ability to cope with stress), recent stress experiences, and quality of life (QOL) was performed in 17 SSc patients and in 38 healthy volunteers. Physical QOL state was impaired in patients, but there were no differences in recent stress experiences and SOC scores between patients and controls. Basal serum cortisol levels were similar in patients and controls, but increased levels of proinflammatory cytokine and noradrenalin were seen in SSc patients. Characteristically, contrary to the control group, whose cortisol levels increased significantly following the mental calculation stress test, no significant increase was observed in the patients when post-test cortisol levels were compared to pre-test levels, suggesting a defect in the normal cortisol response upon stress in SSc patients. The present results suggest that there may be impaired function of the neuro-endocrine-immune system upon stress in SSc patients.

症例は28歳,女性.労作時息切れを主訴に近医受診し,胸写上肺動脈拡張を指摘され当科入院.膠原病を疑わせる検査所見あるも診断基準を満たさず,心臓カテーテル検査などの結果より原発性肺高血圧症と診断し退院.退院後1ヵ月頃より蝶形紅斑および抗二本鎖DNA抗体が出現したことより全身性エリテマトーデス(SLE)の診断が確定したため,ステロイド投与および血漿交換を行ったところ, 4ヵ月後の心臓カテーテル検査にて肺動脈圧および肺血管抵抗の低下を認めた. SLEに肺高血圧症を伴う例のあることは知られているが,肺高血圧症がSLEの診断に先行することは極めてまれである.また原発性肺高血圧症の20～30%にレイノー現象,関節炎,免疫反応の異常など全身性疾患を示す所見を有するものが認められ,これらに対するステロイドなどの免疫抑制療法の可能性を考えるうえで参考になる1例と思われた.

Behçet's disease is a multisystem inflammatory disorder with unknown etiology. It has been shown that the titer of plasma complement component 9 (C9) is a good indicator of the disease activity. Therefore, the involvement of C9 in the pathogenesis of Behçet's disease has been suggested. We report a case of Behçet's disease associated with complete C9 deficiency (C9D) carrying the homozygous nonsense mutation at Arg-95 of C9 (R95X). The patient presented the typical characteristics of Behçet's disease, such as uveitis, recurrent oral aphthae and genital ulcers, and arthritis, suggesting that C9 does not play an essential role in the pathogenesis of Behçet's disease.

We describe a patient who presented with flexion contractures of the bilateral fingers due to tenosynovitis of the flexor digitorum tendons as an initial manifestation of systemic lupus erythematosus (SLE). A 17-year-old woman had abrupt onset of diffuse swelling and flexion contractures in the bilateral fingers, accompanied by polyarthritis and cervical lymphadenopathy. Magnetic resonance imaging (MRI) showed flexor tenosynovitis of the hands. A diagnosis of SLE was made by immunological and hematological tests, and treatment with oral corticosteroids resulted in a rapid and complete disappearance of the flexion contractures.

To elucidate the mechanism of vascular thrombosis in patients with systemic lupus erythematosus and the lupus anticoagulant changes in factors associated with haemostasis were investigated. The lupus anticoagulant was associated with an increased incidence of thrombosis, particularly cerebral thrombosis. Concentrations of fibrinopeptide A and fibrinopeptide B beta 15-42 were significantly raised in the plasma of patients with systemic lupus erythematosus and the anticoagulant compared with concentrations in patients without the lupus anticoagulant. The tendency towards formation of thrombosis was not found in all lupus patients with the anticoagulant, however. Concentrations of thromboxane B2 were remarkably raised in the plasma of the two patients with the lupus anticoagulant who had recently had thrombosis. Concentrations of 6-keto-prostaglandin F1 alpha, protein C, antithrombin III, and plasminogen were similar in both groups. No significant decrease in serum stimulatory activity on prostacyclin production by cultured aortic endothelial cells was noted in lupus patients with the anticoagulant, but inhibition was present in the two patients with recent thrombosis. These results indicate that although patients with the lupus anticoagulant are not always in a hypercoagulable state, haemostatic abnormalities found in some patients with the anticoagulant may be predictive of thrombotic events.

To determine whether there is an intrinsic defect in T cells from patients with systemic lupus erythematosus (SLE), we studied signal transduction systems, assaying the total protein kinase C (PKC) levels and the phorbol myristate acetate (PMA)-induced activation of PKC in PHA-treated T cells. T cells from SLE patients showed a decrease in proliferation in response to PMA, but not to PHA, thereby suggesting the existence of an intrinsic abnormality in the PKC-mediated activation pathway. Total PKC activity in the T cells from SLE patients was significantly decreased. Although stimulation with PMA induced a translocation of PKC from the cytosol to the particulate fraction, translocated PKC activity after 2 nM PMA treatment was decreased in the SLE T cells. Furthermore, PMA-induced phosphorylation of 80-kDa substrates was also decreased in SLE T cells. These results suggest that there is a reduced PKC activity and an impaired PKC activation in response to PMA in the SLE T cells, a finding which may explain, if partially, the defect in T cell activation in patients with SLE.

Mixed connective tissue disease (MCTD) is characterized as a benign rheumatic disease with a favorable response to therapy. When pulmonary hypertension is a complication, however, it is often reported to be fatal. A 32-year-old female patient with MCTD who had developed rapidly progressive pulmonary hypertension and disseminated intravascular coagulopathy was admitted to our hospital and was successfully treated with corticosteroids and anticoagulants. The failure of microcirculation due to coagulopathy is considered to be one of the possible entities of pulmonary hypertension.

50歳の男性が両側足,手,肘関節と左膝関節痛および腰痛にて入院した.腰部の屈曲制限を認め,検査成績ではHLA B27陽性,リウマトイド因子陰性,血沈は1時間値158 mm. X線では仙腸関節や疼痛部の関節に異常なく,腰椎に軽度の骨きょくを認めた.骨シンチグラムでは両側足関節,踵骨,手関節,右第1指MPと第2指PIP関節で取込みを認めた.以上よりseronegative spondyloarthropathy,なかでも仙腸関節に異常を認めないが,強直性脊椎炎を疑った. 5年間の経過中,血沈の上昇をともなった腰背部,後頚部痛および末梢の関節炎を数回繰り返したが, X線では腰椎,仙腸関節,末梢関節ともに異常を見いだしえなかった.本症例はHLA B27陽性,高齢発症,脊椎に比べ末梢関節炎が強い,炎症所見が強い, X線上脊椎と仙腸関節に異常を認めないなどの特徴を有しており,最近DubostとSauvezieが提唱したlate onset peripheral spondyloarthropathyの概念に近い1例と考えられた.

We investigated the incidence of herpes zoster (HZ) and the immunological state to HZ in patients with rheumatoid arthritis (RA) and mixed connective tissue disease (MCTD) in comparison with systemic lupus erythematosus (SLE). HZ occurred in 6 (25%) out of 24 patients with RA and 4 (22%) out of 18 patients with MCTD. One patient had had HZ before the diagnosis of RA. On the other hand, all 4 patients with MCTD had had HZ before the diagnosis of MCTD. The patients with RA and MCTD showed normal or higher antibody titers to varicella zoster virus (VZV) than normal subjects as assayed by both complement fixation technique and neutralization test. However, the antibody levels were not very high compared to those in patients with SLE. On the other hand, only 7 (50%) of 14 patients with RA and 4 (40%) of 10 patients with MCTD showed positive skin reactions to VZV antigen, whereas all 15 normal subjects had positive reactions. Thus, cellular immunity to VZV was thought to be impaired in these diseases. In the patients who were receiving less than 10 mg/day of prednisolone, 7 (64%) of 11 had positive skin reactions in RA patients and 3 (60%) out of 5 patients with MCTD, whereas none (0%) out of 3 patients with RA and 1 (20%) out of 5 patients with MCTD who were receiving 10 mg/day or more prednisolone showed positive skin reactions. These results suggest that the high incidence of HZ in patients with RA and MCTD is probably due to an impaired cellular immunity as in the case of SLE.

Four cases of nocardiosis in patients with adult-onset Still disease and vasculitis syndrome are presented. Three patients developed lung abscesses and 1 case developed a brain abscess. All were treated with high-dose corticosteroids, and 3 were given cyclosporine when they developed nocardiosis. All patients were successfully treated with antibiotics; cyclosporine was discontinued in 2 cases. These cases indicate that systemic nocardiosis can develop in patients with various rheumatologic diseases who are treated with corticosteroid and immunosuppressive drugs such as cyclosporine.

The incidence of herpes zoster was determined in patients with systemic lupus erythematosus (SLE) and the cellular and humoral immunity to varicella zoster virus (VZV) investigated in 45 of these 92 patients. The incidence of herpes zoster was high, occurring in 40 patients (43%), though it was benign in all. Patients with SLE who had had zoster showed significantly higher antibody titres than normal subjects. On the other hand, only 13 of 43 (30%) patients with SLE showed positive delayed hypersensitivity skin reactions to VZV antigen, despite a history of infections with VZV, whereas all 15 normal subjects had positive reactions. Skin reactions to VZV correlated directly with the ratio of OKT4+ to OKT8+ T cells and inversely with the dose of corticosteroids. These results suggest that the high incidence of herpes zoster in patients with SLE is probably due to defects in cellular immunity and that normal or higher titres of antibodies to VZV will not act as a preventive against zoster. In addition, reactivation of VZV, whether symptomatic or not, seemed often to occur in patients with SLE.

The clinical importance of IgG anticardiolipin antibodies was investigated in systemic lupus erythematosus (SLE). IgG anticardiolipin antibodies were found in 69 of 155 (44.5%) patients with SLE. Serial measurements of IgG anticardiolipin antibodies allowed the patients to be classified into two groups: group A, persistently positive for IgG anticardiolipin antibodies; group B, positive only in active phases. The IgG anticardiolipin antibody titre in group A was significantly higher than in group B. The incidence of thromboses, spontaneous abortions, and lupus anticoagulant in group A was significantly higher than in group B (p less than 0.05). By contrast, the incidence of renal diseases and anti-dsDNA antibodies in group B was significantly higher than in group A (p less than 0.05). This study showed that group A formed a separate subgroup of patients with SLE who had a high risk of thromboses and spontaneous abortions despite having milder disease activity.