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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.

Point-of-care diagnosis of influenza requires sound recognition of the prevalence of the signs and symptoms of the patients, which would help to define the pattern of clinical presentation of this infection. In severely ill patients, however, clinical features of influenza could be erroneously modified by the exacerbation of co-morbid conditions, resulting in a delay of the diagnosis. Enzymatic rapid diagnostic tests, although establishing the diagnosis with positive result especially when the virus is in high circulation, has relatively poor sensitivity for the 2009 A/H1N1 virus and it varies among the different age groups. Given the likelihood of long-term circulation of the novel H1N1 virus, patients' clinical features and the performance of the rapid tests should continuously be monitored.

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.

Okadaic acid is a potent tumor promoter and an inhibitor of serine/threonine-specific protein phosphatases. We studied the effect of okadaic acid in human T cell activation and phosphorylation of internal substrates. Okadaic acid at up to 4 nM enhanced phorbol myristate acetate (PMA)-induced proliferation and CD25 (IL-2 receptor, p55) expression, although it showed no activation by itself. Okadaic acid induced hyperphosphorylation of a 60 kDa protein in T cells as well as non-T cells, as reported in fibroblasts and keratinocytes. Preincubation with 4 nM okadaic acid enhanced PMA induced phosphorylation of the 80 kDa protein, an internal substrate of protein kinase C in T cells. These results suggest that okadaic acid inhibited dephosphorylation of protein kinase C specific substrates, and as a result, enhanced T cell activation mediated by protein kinase C pathway.

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.

種々のリウマチ性疾患患者を対象にして,血漿中の補体分解産物C 4 d, iC 3 bおよびBb濃度をモノクローナル抗体を用いたEIAキットを用いて測定し,血清補体価,補体成分および免疫複合体量との関連を検討した.一般に低補体血症を示す全身性エリテマトーデスだけでなく,高補体血症を示す慢性関節リウマチや大動脈炎症候群, Behget病などの炎症性結合組織疾患でも血漿中のC 4 d, iC 3 bおよびBbが増加しており,とくにBbの増加するものが多くみられた.全身性エリテマトーデス,混合性結合組織病,多発性筋炎,強皮症および慢性関節リウマチでは補体分解産物の間に相関を認めなかったが,大動脈炎症候群とBehcet病においてC 4 dとiC 3 bとの間に正の相関を認めた.全身性エリテマトーデスにおいてC 4 dが免疫複合体量と正の,血清補体価と負の相関を示したが, iC 3 bとBbは免疫複合体量や血清補体価との相関を示さなかった.以上,種々のリウマチ性疾患において,免疫複合体による補体古典的経路の活性化だけでなく,補体第2経路の活性化をも生じていることが示唆された.今後,各々の症例で補体分解産物を測定することは,補体活性化の関与する病態の解明に有用であると思われる.

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.

全身性エリテマトーデス(SLE)の病態形成における補体系の関与をより明らかにするため,当科に入院した活動性SLE 60例を対象とし, SLEの臨床症状,検査所見とCH50, C3, C4との関係,臨床経過に伴うCH 50の変化,治療開始6ヵ月後にCH50の正常化した群,しなかった群の差異につき検討した. SLEの臨床症状,検査所見,治療において口腔潰瘍,腎症,溶血性貧血,抗DNA抗体高値,免疫複合体陽性,パルス療法施行群などにて補体が低下していた.臨床経過に伴うCH50の推移では治療前に腎症群で著明低値,一方, CNSループス群で軽度低値を示したが3ヵ月後, 6ヵ月後にはCH50は正常化しほぼ同程度の値となった.治療開始6ヵ月後にCH50が正常化しなかった例は24.3%であり,正常化しなかった群では正常化した群に比し,溶血性貧血の頻度が高く治療前のC4が低値であり,免疫抑制剤の使用頻度が低かった.

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.

We determined the incidence of herpes zoster (HZ) in 119 patients with systemic lupus erythematosus (SLE). HZ occurred in 56 patients (47%), and 9 patients had had HZ even before SLE developed. After diagnosis of SLE, an incidence of zoster was high, 5.45 cases per 100 person-years. It was found that the susceptibility to HZ was not related to the presence of renal disorder or maximum dose of corticosteroids. The patients with SLE who had had HZ showed significantly higher antibody titers than those without a history of HZ and normal subjects as assayed by both complement fixation technique and neutralization test. On the other had, only 17 of 55 patients (31%) with SLE showed positive skin reactions to varicella zoster virus (VZV) antigen, whereas all 15 normal subjects had positive reactions. In the patients who were receiving less than 10 mg/day of prednisolone, 11 of 17 (65%) had positive skin reactions to VZV antigen, whereas only 4 of 31 (13%) patients who were receiving 10 mg/day or more prednisolone showed positive reactions. It was of interest that in 7 patients with SLE who had not received corticosteroids, only 2 (29%) patients showed positive skin reactions to VZV antigen. These results suggest that high incidence of HZ in patients with SLE is probably due to an impaired cellular immunity because of both underlying disease and corticosteroid treatment.

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.

当科の全身性エリテマトーデス(以下SLE)142例を診断時年齢により, 20歳未満の若年群27例, 20歳以上40歳未満の好発年齢群91例, 40歳以上の高齢群24例の3群に分け,臨床症状,予後,とくにこれまで報告の少ない合併症についてretrospectiveに検討した.従来の報告どおり,蝶形紅斑,口腔潰瘍,発熱,腎症,とくにネフローゼ症候群を呈する症例が若年群に多かった.しかし,今までの報告と異なり漿膜炎,とくに心膜炎の頻度が若年群に有意に多くみられた.検査成績でも,若年群は従来報告されているように,低補体の頻度,抗DNA抗体の陽性率が高く,治療でも大量のステロイド剤を必要とする傾向にあり,パルス療 法,免疫抑制剤の併用率も高かった.合併症では大腿骨頭壊死が有意に若年群に多く,若年発症は危険因子の1つと考えられた.一方,帯状疱疹,血栓症は各群ともほぼ同じ頻度で合併しており,年齢との関係はみられなかった.若年群は予後も不良であり,若年発症は予後不良因子と考えられた.一方,今回の検討では高齢群に大きな特徴はみられなかった.

リンパ節腫大を伴う高ガンマグロブリン血症がみられて5年後に全身性エリテマトーデス(SLE)の確定診断が得られた症例を報告する.症例は33歳の女性. 28歳時,血液検査で偶然に高ガンマグロブリン血症を指摘され入院.自覚症状はなく,理学的には左側頚部に数個の小豆大のリンパ節腫大を認めるのみであった. LE細胞現象は陰性で,抗核抗体,抗DNA抗体は弱陽性であった.リンパ管造影で両そけい部から腹部大動脈周囲にかけてリンパ節の腫大を認め,リンパ節生検にて形質細胞の増生がみられた. SLEが疑われたが, ARA診断基準(1971年)を満たさず,特発性高ガンマグロブリン血症またはlatent SLEの診断の下で経過観察をしていた. 5年後に全身倦怠感,起床時の手指のこわばり,発熱,脱毛が出現, SLEの確定診断が得られた.本症例はSLEの確定診断以前の病態を把握しており, SLEの進展ならびに自然経過を考えるうえで興味ある症例と思われた.

赤芽球ろうから自己免疫性溶血性貧血を伴った全身性エリテマトーデスに移行した1例を報告する.症例は27歳女性で発熱,関節痛,筋肉痛にて入院. Hb 6.6g/dlと貧血を認め,尿ウロビリノーゲン(3+),直接クームステスト陽性,ハプトグロビン

Interstitial lung disease (ILD) associated with polymyositis (PM) and dermatomyositis (DM) sometimes progresses rapidly and is resistant to therapy. Clinical features that forecast the prognosis of the disease remain to be elucidated. Our aim was to assess if selected clinical features and high-resolution computed tomography (HRCT) findings can assist in predicting the clinical course of ILD in PM/DM.We examined HRCT findings retrospectively for ILD identified in 17 patients with PM and 16 with DM. Radiological patterns and clinical features are analyzed in comparison with clinical course.Mortality rates were 12% and 44% for ILD associated with PM and DM, respectively. Most patients with DM died of rapidly progressive lung deterioration. No patient in the PM group died of respiratory failure. In the DM group, all patients with fatal ILD had ground-glass attenuation and reticular opacity as the principal radiological findings. Consolidation was recognized frequently as the principal pattern in nonfatal cases. Radiological patterns were categorized into 3 groups; A: consolidation dominant, B: ground-glass attenuation/reticular opacity dominant without chronic fibrosing process, and C: ground-glass attenuation/reticular opacity dominant with chronic fibrosing process. Occurrences of fatal disease were 0%, 83%, and 20%, in groups A, B, and C.The prognosis of ILD associated with DM differs from that with PM. The former can be classified into 3 subgroups on the basis of radiological findings, which are closely associated with clinical course.

Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS) and other exogenous and endogenous molecules, and is thought to contribute to defense mechanisms against infections. Our objective was to elucidate the clinical significance of TLR4 in acute infectious diseases by analyzing its sequential expression on CD14+ monocytes. Peripheral blood samples were obtained from 36 patients with acute infectious diseases on admission and after treatment within certain intervals. The TLR4 expression on CD14+ monocytes was analyzed using flow cytometry and was presented as a mean fluorescence intensity (MFI). TLR4 expression during the acute phase of infection was highly enhanced compared to that of normal subjects (MFI: 22.1 vs 8.5). TLR4 expression was promptly reduced to normal levels in parallel with the disease improvement. In patients who died despite treatment, the enhancement of TLR4 expression during the acute phase was less prominent compared to those who survived (MFI: 14.6 vs 23.5) and its sequential change was also subtle. These results indicate that monocytes respond to acute infections by the induction of TLR4 expression and that a poor response may be associated with a poor prognosis.

Objectives: To perform a case–control study of a functional M196R polymorphism of tumour necrosis factor receptor type 2 (TNF-RII) in a Japanese population and a meta-analysis of all published reports on the polymorphism to investigate the association of the M196R polymorphism of TNF-RII with systemic lupus erythematosus (SLE). Methods: The functional M196R polymorphism of TNF-RII was genotyped by using polymerase chain reaction combined with the subsequent single-strand conformation polymorphism (PCR—SSCP) analysis for screening, followed by nucleotide sequencing for confirmation. A total of 331 patients and 359 controls were subjected to a case–control study. A meta-analysis of the available case–control studies including all published data as well as our own data was performed to investigate the association of the functional M196R polymorphism of TNF-RII with SLE. Results: Our case–control study did not show any significant association of a functional M196R polymorphism of TNF-RII with SLE, although there was a trend towards association. A meta-analysis of seven case–control studies in eight different ethnic populations including our own showed that 196M/R and 196R/R genotypes combined was significantly associated with an increased risk of SLE (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.04 to 1.60; p = 0.02). Stratification by ethnicity showed a more significant association in Asians, including Japanese, Korean and Vietnamese (OR 1.40, 95% CI 1.10 to 1.78; p = 0.006). The effect of the 196R allele on SLE was not clear in Caucasians. Conclusions: The 196R allele of the functional M196R polymorphism of TNF-RII is a risk factor for SLE, especially in the Asian population.

We investigated the effect of hepatocyte growth factor (HGF) on collagen metabolism in cultured fibroblasts from scleroderma (SSc) patients and discussed the possible mechanism of its effect. Synthesis of matrix metalloproteinase-1 (MMP-1) and collagen and mRNA levels of various cytokines were examined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction, respectively. Hepatocyte growth factor enhanced MMP-1 production and mRNA levels of MMP-1 and Ets-1 (a transcriptional factor of MMPs). In addition, HGF suppressed collagen synthesis and mRNA levels of procollagenalpha1(I) and connective tissue growth factor (CTGF) in SSc fibroblasts. Expression of transforming growth factor (TGF)-beta1 was not inhibited significantly in SSc or control fibroblasts. Hepatocyte growth factor also increased interferon (IFN)-gamma mRNA significantly in SSc and control fibroblasts. Addition of anti-HGF antibody neutralized these effects of HGF on MMP-1 and collagen synthesis. The results suggest that HGF can suppress collagen accumulation in SSc fibroblasts by increasing MMP-1 levels possibly via activation of Ets-1 and also by decreasing collagen synthesis, which may be partly related to inhibition of CTGF, and increasing IFN-gamma levels rather than the effect on TGF-beta1. The present study indicates that HGF may be a promising therapeutic agent for this intractable disease.

Many risk factors have been proposed for systemic lupus erythematosus (SLE). However, there is little information about the relationship between lifestyles and SLE in Japan. Two case control studies were conducted in Kyushu, southern Japan, and in Hokkaido, northern Japan, to examine the relationship between lifestyles and development of SLE in females. The participants were 78 patients and 329 controls in Kyushu and 35 patients and 188 controls in Hokkaido. Smoking was associated with an increased risk of SLE after adjusting for age in both regions. However, in Hokkaido, this association between smoking and SLE did not reach statistical significance after adjusting for alcohol drinking. The present study suggests that smoking may increase the risk of SLE among Japanese females.

Objectives: To carry out a phase I-II trial to elucidate the feasibility and efficacy of high dose cyclophosphamide (CY) supported by autologous peripheral blood stem cell transplantation (PBSCT) in the treatment of severe and refractory autoimmune disease (AD). Methods: Peripheral blood stem cells (PBSCs) were mobilised during haematological recovery after relatively high dose CY (2 g/m 2 ) for 2 days, followed by administration of granulocyte colony stimulating factor. After collecting PBSCs—more than 2×10 6 CD34+ cells/kg—by apheresis, CD34+ cells were immunologically selected and cryopreserved. Eight patients were enrolled—five had systemic sclerosis (SSc) alone, one had SSc with systemic lupus erythematosus, one amyopathic dermatomyositis (ADM), and one Wegener’s granulomatosis (WG). All of the patients were treated with high dose CY (50 mg/kg) for 4 days and autologous PBSCT. Results: Haematopoietic reconstitution was rapid and sustained. Toxicity due to the regimen included various infections such as pneumonia, sepsis, cystitis, herpes zoster, and acute heart failure. However, there was no treatment related mortality. Encouraging results were obtained after autologous PBSCT. Sclerosis of the skin was markedly improved in all of the patients with SSc. Interstitial pneumonia (IP), evaluated by Pao 2 , serum KL-6 levels, and pulmonary high resolution computed tomography, improved significantly. In a patient with ADM, severe and progressive IP also improved markedly. In a patient with WG, the size of the left orbital granuloma decreased substantially, resulting in reduction of the exophthalmos. Conclusions: These observations suggest that high dose CY with autologous PBSCT is feasible and may be effective in the treatment of severe and refractory AD.

The objective of this study was to define prospectively the early development of corticosteroid-induced osteonecrosis of femoral head (ONF) in patients with systemic lupus erythematosus (SLE) and to identify the association of initial steroid treatment with the development of early (silent) ONF. Forty-five patients who were newly diagnosed as having SLE and required 40 mg/day or more prednisolone were enrolled. To detect silent ONF, examinations using magnetic resonance imaging (MRI) were done three months after starting steroid therapy, followed by every year’s MRI and plain radiography for over five years. Clinical and laboratory data were compared between silent ONF and non-ONF groups. Of 45 patients, 15 (33%) developed silent ONF and five (11%) symptomatic ONF. It was of interest that MRI detected silent ONF very early (by three months) in 14 patients (93%). It should be noted that pulse therapy with 1000 mg/day methylprednisolone was found to be done very frequently (13 of 15, 87%) in the silent ONF group compared to non-ONF group (11 of 30, 37%) (P, 0.01) although other clinical features were not significantly different between both groups. High dose corticosteroids caused elevation of serum levels of total cholesterol, albumin, and leukocyte count in most of patients. The degree of elevation of those parameters at one or three months was more prominent in the silent ONF group. In particular, the change ratio of total cholesterol at one month was outstanding in the silent ONF group compared to non-ONF group (0.551 versus 0.374, P, 0.05). In conclusion, pathological ONF develops very early in one-third of SLE patients who received high dose corticosteroids and steroid pulse therapy could be a significant risk factor. An abrupt elevation of serum total cholesterol and/or sensitivity to steroids seem to be associated with the pathogenesis of ONF.

B cells lacking RP105 molecule, a member of the Toll-like receptor family, were increased in the peripheral blood of 2 patients with antinuclear antibody (ANA) negative systemic lupus erythematosus (SLE). The increased proportion of RP105-lacking B cells was associated with disease activity in patients with ANA-negative SLE. When there are no significant serological markers for SLE, analysis of expression of RP105 may be helpful in evaluation of activity in ANA-negative SLE. We describe a new approach, using phenotyping of B cells, to evaluate activity of ANA-negative SLE.

Circulating cell-free nucleic acids are noninvasive diagnostic tools for cancer detection. Heterogeneous nuclear ribonucleoprotein (hnRNP) B1, an RNA binding protein, has been found overexpressed in the early stage of lung cancer, including bronchial dysplasia, a premalignant lesion of lung squamous cell carcinoma. To determine the utility of plasma hnRNP B1 RNA and as cancer detection markers for lung cancer, we analyzed plasma hnRNP B1 mRNA of lung cancer patients by real-time RT-PCR. Plasma RNA was extracted from plasma of 44 lung cancer patients, 7 lung neoplasm patients, 24 benign lung diseases and 25 healthy volunteers. Mean concentration of plasma hnRNP B1 mRNA in lung cancer patients was 0.99 pg/microg RNA, whereas that in healthy volunteers and in benign lung diseases was 0.23 pg/microg RNA and 0.30 pg/microg RNA, respectively (p

TLR4 and RP105 are unique members of the Toll-like receptor (TLR) family molecules. They are associated with small molecules called MD-2 and MD-1, respectively, to form heterodimers (TLR4/MD-2 and RP105/MD-1) and function as recognition/signaling molecules of lipopolysaccharide (LPS), a membrane component of Gram-negative bacteria. Analysis of transfectant cell lines and gene-targeted mice revealed that both MD-2 and MD-1 are involved in the recognition of LPS as well as in the regulation of intracellular distribution and the surface expression of TLR4 and RP105, respectively. Since RP105 or MD-1-deficient mice show a reduced but not complete lack of LPS responsiveness, there may be functional associations between TLR4/MD-2 and RP105/MD-1. In addition, there was an increased frequency of RP105-negative B-lymphocytes in the peripheral blood in several rheumatic diseases, such as systemic lupus erythematosus, suggesting the involvement of RP105 in the pathophysiology of autoimmunity. Further analysis of the structure and function of TLR4/MD-2 and RP105/MD-1 will provide a better understanding of the pathophysiology, and a chance to develop evidence-based treatments for septic shock syndrome and autoimmunity.

To examine the frequency of depressive symptoms and also to identify factors closely associated with their development in patients with scleroderma (systemic sclerosis, SSc).We evaluated 50 patients with SSc for factors associated with depressive symptoms using the following established scales: the Beck Depression Inventory (BDI); the Rheumatology Attitude Index for measuring helplessness; the Sense of Coherence (SOC) scale (a measure of an individual's resilience in the face of stress and capacity to cope with it); the modified Health Assessment Questionnaire for physical disability, working, and social function; support domains of Arthritis Impact Measurement Scales version 2; and a visual analog pain scale. In addition, disease severity of SSc, including skin thickness and internal organ involvement, was also examined in each patient. Multiple regression analysis was used to determine which factors correlated with depressive symptoms.Depressive symptoms ranging from mild to severe state were seen in 46% of the patients. Total BDI scores were significantly correlated with low working ability, low social activity, low SOC, pain, and helplessness, and not associated with disease severity variables including skin score and internal organ involvement. Multiple regression analysis showed that a high level of helplessness and a low level of SOC might be closely associated with depressive symptoms in SSc.Our results indicate that depressive symptoms are frequent in SSc patients. Medical staffs should pay attention to the possible risk factors for depressive symptoms, such as patient's helplessness and SOC.

Accumulating evidence suggests that eosinophils play an important role in the pathogenesis of allergic diseases. An eosinophil-active chemokine, eotaxin, and its receptor, C-C chemokine receptor 3, are particularly attractive as novel targets of immunological intervention for the disease. In this study, we examine the effects of a hexa-peptide (Ac-RRWWCR-NH 2 ), Antileukinate, which we have previously defined as a potent inhibitor of CXC chemokine receptor 1 and 2, on eotaxin in vitro and in vivo. Antileukinate inhibited the binding of 125 I-labeled human eotaxin to human eosinophils with an IC 50 of approximately 10 μM and eosinophil chemotaxis to human eotaxin was significantly inhibited by 10 μM of Antileukinate. We examined the effects of Antileukinate on eosinophil accumulation induced by intraperitoneal administration of murine eotaxin, and confirmed that Antileukinate is also active in the murine system. When Antileukinate was tested in ovalbumin-induced airway inflammation model in vivo, Antileukinate significantly inhibited eosinophil accumulation and allergen-induced increase in total protein in bronchoalveolar lavage fluids. Furthermore, Antileukinate suppressed fibrous thickening of submucosal tissue induced by chronic antigen challenge. These results suggest that eotaxin is involved in the pathogenesis of eosinophilic airway inflammation, and that Antileukinate may be a promising tool to control allergic diseases.

We investigated the features and the usefulness of gallium scintigraphy in the diagnosis and the assessment of Adult Still's disease (ASD) by retrospective case review. Gallium scintigraphy have been done for 11 cases of ASD (3 males and 8 females) and 4 females were positive. Among these, 67 Ga-citrate was accumulated to the bone marrow in all 4 cases and to the major joints in 2 cases. Positive cases were rather serious and administered more immunosuppressants than negative cases. In order to characterize gallium scintigraphy findings of ASD, i.e. bone marrow accumulation, we analyzed 130 cases of collagen vascular diseases. Although 101 cases (77.7%) were positive, only 7 cases (5.4%) showed the accumulation of 67Ga-citrate to the bone marrow. These include 3 cases with ASD, and 1 case with systemic lupus erythematosus, polyarteritis nodosa, Wegener's granulomatosis and Sjögren's syndrome. We also accumulated 18 patients who exhibited bone marrow accumulation of 67Ga-citrate, and found that 7 patients had collagen vascular and their related diseases. In conclusion, bone marrow accumulation in gallium scintigraphy is a specific feature of collagen vascular diseases, especially ASD, and it is suggested that cases with positive gallium scintigraphy in ASD can be serious and resistant to treatment.

Objective We previously reported that B cells lacking the RP105 molecule, which proved to be highly activated B cells, are increased in the peripheral blood of patients with systemic lupus erythematosus (SLE). In the present study, we attempted to determine whether RP105-negative B cells obtained from SLE patients would be capable of producing autoantibodies as well as immunoglobulins. Methods RP105-positive and RP105-negative B cells, sorted by cell sorter, were cultured for 5 days without stimulation, or were stimulated with Staphylococcus aureus Cowan 1 strain (SAC) or recombinant interleukin-6 (IL-6). For the assay of autoantibodies, RP105-positive and RP105-negative B cells were cultured separately for 10 days with anti-CD3 antibody–stimulated T cells. The production of immunoglobulins and autoantibodies was determined by enzyme-linked immunosorbent assay. Results We demonstrated that RP105-negative B cells, but not RP105-positive B cells, obtained from SLE patients could spontaneously produce IgG and IgM in vitro until day 5. SAC and IL-6 enhanced production of IgG and IgM by RP105-negative B cells but failed to induce such production by RP105-positive B cells. The latter cells, however, when cocultured with activated T cells in the presence of IL-10, produced IgG, although the amount was very small compared with that produced by RP105-negative B cells. Most important, under these conditions, anti–double-stranded DNA antibodies were produced only by the RP105-negative B cells obtained from SLE patients. Conclusion These data indicate that RP105-negative B cells, constituting a subset of B cells in SLE patients, are highly activated and may be responsible for the production of autoantibodies as well as polyclonal immunoglobulins.

A case is reported of a 56-year-old male who presented with bilateral pleural effusion as an initial manifestation of idiopathic fibrosing mediastinitis. The patient showed shortness of breath with severe loss of vital capacity and weight loss. A mediastinal mass surrounding the thoracic aorta and bilateral pleuritis was identified by the chest CT scan. The mass extended, along the abdominal aorta, to the upper portion of retroperitoneum. Laboratory data showed elevated levels of C-reactive protein (CRP), erythrocyte sedimentation ratio (ESR), and IgG. Biopsy of the mediastinal and the pleural mass showed adipose tissue and fibrosis with mild perivascular inflammatory infiltration. A diagnosis of idiopathic fibrosing mediastinitis was made, and 40 mg/day of prednisolone was administered. Although CRP and ESR was normalized, the mass size and vital capacity were almost unchanged.

Objective To investigate whether a polymorphism(s) or mutation(s) in the tumor necrosis factor receptor II (TNFRII) gene is involved in the pathogenesis of systemic lupus erythematosus (SLE). Methods All 10 exons of the TNFRII gene were analyzed by exon-specific polymerase chain reaction–single-strand conformation polymorphism, followed by nucleotide sequencing of exons that displayed aberrant bands. To analyze the function of the TNFRII polymorphisms, the full-length TNFRII complementary DNA of each allele was transfected in HeLa cells and then studied for specific binding of 125I-TNFα, as well as interleukin-6 (IL-6) production and cytotoxic activity after treatment with recombinant human TNFα. Results We identified 4 polymorphisms, at codons 56, 181, 196, and 232. The latter 2 had amino acid substitutions M196R and E232K, respectively. Only the 196R allele was significantly associated with SLE in our 105 Japanese SLE patients, with an allele frequency of 20.5%, compared with 12.6% in 99 healthy controls (P = 0.0335). More importantly, using TNFRII-transfected HeLa cells, we demonstrated significantly increased IL-6 production by 196R TNFRII compared with 196M TNFRII. The cytotoxic activity induced by 196R TNFRII was also increased compared with that of 196M TNFRII. This increase was achieved without affecting the binding affinity of TNFα to TNFRII, as demonstrated by the finding that specific TNFα binding to the HeLa transfectants of 196R and 196M TNFRII was similar, with Kd values of 3.12 × 10−10M and 4.34 × 10−10M, respectively. Conclusion These results suggest that 196R TNFRII, which transduces the signals of TNFα more effectively than does 196M TNFRII, is involved in the pathogenesis of SLE.

A case is reported of a 29 year old female who had autoimmune hepatitis associated with mixed connective tissue disease (MCTD). The patient developed MCTD at the age of 19, and was treated with prednisolone. Liver dysfunction developed 7 years later, which exacerbated shortly after the patient suffered intrauterine fetal death during the second trimester of pregnancy. Laboratory data showed negative anti-hepatitis C antibody and hepatitis B antigen, but positive anti-smooth muscle antibody. A liver biopsy showed chronic active hepatitis. Referring to the criteria we diagnosed her as having autoimmune hepatitis. Although hepatomegaly is sometimes observed in MCTD patients, only 5 cases of autoimmune hepatitis associated with MCTD have been reported in the past. In our case, it is of note that autoimmune hepatitis developed while symptoms of MCTD were in remission, and that autoimmune hepatitis exacerbated with the emergence of anti-smooth muscle antibody following the termination of pregnancy.

Auteur(s) : Noriyuki Misago1, Hisako Inoue1, Takuya Inoue2, Kohei Nagasawa2, Yutaka Narisawa1 1Dermatology, Department of Internal Medicine, Faculty of Medicine, Saga University, Nabeshima 5-1-1, Saga 849-8501, Japan 2Rheumatology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan A 31-year-old female presented with a relapsing fever of 39 °C and a rash of one week’s duration after sun-exposure. She had no history of medication. She displayed [...]

A 72-year-old woman with 5-year history of essential hypertension developed peritoneal tuberculosis. The patient's hypertension, which had been well-controlled by long-acting nifedipine, deteriorated after the administration of rifampicin, an antitubercular agent. During use of nifedipine and rifampicin, both the peak plasma concentration and the area under the curve of nifedipine decreased markedly to about 40% of those without rifampicin. The findings suggest that rifampicin may increase the elimination of nifedipine, presumably by induction of its hepatic metabolism. Nisoldipine, another calcium antagonist, also failed to lower the patient's blood pressure, when given in combination with rifampicin. Taken together, these findings indicate that more caution should be urged when calcium antagonist is prescribed along with rifampicin.

Objective—To investigate the incidence of retinopathy in systemic lupus erythematosus (SLE) and to clarify its significance in relation to other clinical manifestations. Methods—A cross sectional study on lupus retinopathy was made in 69 patients with SLE. One expert ophthalmologist examined the ocular fundi of the lupus patients without any information of their disease state. Clinical and laboratory findings in the patients with retinopathy and those without were compared. Results—Retinopathy was found in 7/69 (10%) patients. The findings included haemorrhages, vasculitis, cotton wool spots,and hard exudates,all of which were considered to reflect vascular damage. Retinopathy was found to be associated with the presence of anticardiolipin antibody (p