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Objective: To determine whether tumor necrosis factor (TNF) blockade improves small airway obstruction in rheumatoid arthritis (RA) patients without apparent respiratory symptoms.Methods: Pulmonary function tests were performed before and one year after TNF blockade therapy in 29 RA patients without apparent respiratory symptoms. As a control, pulmonary function was examined at a one-year interval in 27 RA patients with conventional disease-modifying antirheumatic drugs (DMARDs) alone. Small airway obstruction was diagnosed when one of maximal mid-expiratory flow rate (MMEF), forced expiratory flow at 50% (FEF50) or 75% (FEF75) of the vital capacity was decreased to less than 60%, 55%, or 45% of predicted values, respectively.Results: Small airway obstruction was found in 62.5% of RA patients. No differences were found in age, sex, disease duration, or disease activities. TNF inhibitors dramatically reduced disease activities. However, TNF inhibitors failed to improve small airway obstructions but worsened them.Conclusions: TNF blockade fails to improve small airway obstruction, suggesting that TNF-independent pathways play important roles in the development of small airway obstruction in RA.

To clarify the differences and similarities in the cytokine profiles of macrophage activating syndrome (MAS) between systemic lupus erythematosus (SLE) and adult-onset Still's disease (AOSD). The study participants included 9 patients with MAS-SLE, 22 with non-MAS-SLE, 9 with MAS-AOSD, and 13 with non-MAS-AOSD. Serum cytokine levels were measured using a multiplex bead assay. Cytokine levels were compared between patients with SLE and AOSD with/without MAS. Moreover, cytokine patterns were examined using principal component analysis (PCA) and cluster analysis. IL-6, IL-8, IL-18, and TNF-α levels were elevated in patients with SLE and AOSD. IFN-α levels were elevated in SLE, whereas IL-1β and IL-18 levels were elevated in AOSD. In SLE, IFN-α and IL-10 levels were higher in MAS than in non-MAS and controls. PCA revealed distinctive cytokine patterns in SLE and AOSD, SLE with IFN-α and IP-10, AOSD with IL-1β, IL-6, and IL-18, and enhanced cytokine production in MAS. PCA and cluster analysis showed no differences in cytokine patterns between the MAS and non-MAS groups. However, serum ferritin levels were correlated with IFN-α levels in SLE. Cytokine profiles differed between SLE and AOSD but not between MAS and non-MAS. MAS is induced by the enhancement of underlying cytokine abnormalities rather than by MAS-specific cytokine profiles. Type I IFN may be involved in MAS development in patients with SLE.

Objective We aimed to determine the outcome of combination therapy with tofacitinib (TOF) in a case series of refractory rapidly progressive interstitial lung disease (ILD) associated with anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive (Ab+) DM. Patients who had poor prognostic factors and failed to respond to immunosuppressive therapy were selected for TOF treatment. Methods Five patients with anti-MDA5 Ab+ DM-ILD who failed to respond to triple therapy with high dose glucocorticoids, CSA and CYC were given additional TOF (10 mg/day). To identify the poor prognostic factors, data from 15 consecutive patients (seven survived and eight died) with anti-MDA5 Ab+ DM-ILD before induction of TOF were analysed. Results Three poor prognostic factors were identified: serum ferritin level >1000 ng/ml before therapy; ground-glass opacities in all six lung fields before therapy; and worsening of pulmonary infiltrates during therapy. All six patients who had all of the three factors and received triple therapy died before TOF therapy. There were five patients who had all of the three prognostic factors and failed to respond to triple therapy, but were able to receive the combination therapy with TOF; among them, three survived and two died. The survival rate of patients who received TOF was significantly better than that of the historical controls with immunosuppressive therapy before TOF. The patients who received TOF experienced complicated adverse events, particularly viral infection. Conclusion Combination therapy with TOF might have the potential to control refractory anti-MDA5 Ab+ DM-ILD.

Background: By autoantibodies, myositis is recently classified into subgroups with distinctive clinical features. Cytokines play critical roles in the development of the clinical features. However, it is not fully unknown whether myositis subgroups defined by autoantibodies have unique cytokine profiles. Objectives: To clarify the relationship between cytokine profiles and autoantibodies in myositis. Methods: Subjects were myositis patients who admitted Dokkyo Medical University and whose serum before starting therapy were available. Serum cytokine levels (IL-1a, 1b, 2, 4,5, 6, 10,12, 13,15,17, 23,IFN-g, TNF-a, IFN-a, b,IP-10 and MCP-1) in sera from the patients and controls were measured using Q-Plex™ Multiplex Arrays. Demographic and clinical data were obtained by reviewing medical record retrospectively. Results: Subjects were 45 myositis patients with male/female; 22/23 and 59.4 years of mean age. Amyopathic dermatomyositis (ADM), classical DM and polymyositis (PM) were 21, 11 and12 cases, respectively. Autoantibodies were anti-MDA5+ in 21, anti-ARS+ in18 and anti-TIF1g+ in 5 cases. ILD and malignancy was complicated in 39 and 5 cases, respectively. Serum cytokine levels were measured. As shown in Fig.1, IP-10 levels were increased in all types of myositis patients, but not in controls. In ant-MDA5 Ab + myositis, IL-6, IL-10, IL-15, TNF-a, IFN-a and MCP-1 levels were increased. In anti-ARS Ab+ cases, IFN-b levels were elevated as well as TNF-a and MCP-1. Through the correlation analysis between cytokine levels, cytokine groups were identified (Fig.2). In anti-MDA5 Ab+ cases, 2 cytokine groups were identified; one includes IFN-a, IL-15, TNF-a and IL-10, and the other involved IL-6, MCP-1. Both groups connected with IP-10. In In anti-ARS Ab+ cases, 2 groups were found; one included TNF-a, MCP-1and IP-10, and the other had IFN-b as a sole component. Conclusion: Cytokine profiles differ among subgroups in myositis. In anti-DDA5+ myositis, IL-15 and IFN-a with strong correlation and IL-6 were characteristic cytokines, while IFN-b was a unique one in anti-ARS+ myositis Disclosure of Interests: None declared

Objective: We aimed to analyze the clinical and histopathologic features of cancer-associated myositis (CAM) in relation to anti–transcriptional intermediary factor 1 γ antibody (anti-TIF1-γ-Ab), a marker of cancer association. Methods: We retrospectively studied 349 patients with idiopathic inflammatory myopathies (IIMs), including 284 patients with pretreatment biopsy samples available. For the classification of IIMs, the European Neuromuscular Center criteria were applied. Patients with CAM with (anti-TIF1-γ-Ab[+] CAM) and without anti-TIF1-γ-Ab (anti-TIF1-γ-Ab[−] CAM) were compared with patients with IIM without cancers within and beyond 3 years of myositis diagnosis. Results: Cancer was detected in 75 patients, of whom 36 (48%) were positive for anti-TIF1-γ-Ab. In anti-TIF1-γ-Ab(+) patients with CAM, cancers were detected within 1 year of myositis diagnosis in 35 (97%) and before 1 year of myositis diagnosis in 1. All the anti-TIF1-γ-Ab(+) patients with CAM satisfied the dermatomyositis (DM) criteria, including 2 possible DM sine dermatitis cases, and were characterized histologically by the presence of perifascicular atrophy, vacuolated fibers (VFs), and dense C5b-9 deposits on capillaries (dC5b-9). In contrast, 39 anti-TIF1-γ-Ab(−) patients with CAM were classified into various subgroups, and characterized by a higher frequency of necrotizing autoimmune myopathy (NAM). Notably, all 7 patients with CAM classified into the NAM subgroup were anti-TIF1-γ-Ab(−) and exhibited no dC5b-9 or VFs. Conclusions: CAM includes clinicohistopathologically heterogeneous disease entities. Among CAM entities, anti-TIF1-γ-Ab(+) CAM has characteristically shown a close temporal association with cancer detection and the histopathologic findings of dC5b-9 and VFs, and CAM with NAM is a subset of anti-TIF1-γ-Ab(−) CAM.

Endogenous lipoid pneumonia is an uncommon inflammatory pulmonary disease that is caused by lipids from an endogenous source, the treatment for which has not been established. We report the first case of endogenous lipoid pneumonia presenting as lung consolidation and which was associated with rheumatoid arthritis. Treatment was successful with intensive immunosuppressive therapy. When a physician finds lung consolidation in a patient with active rheumatic disease, lipoid pneumonia should be considered.

To clarify the clinical features of organizing pneumonia (OP) associated with rheumatoid arthritis (RA) and to determine whether development of OP is related to RA activity.A cross-sectional study was conducted, in which medical records of 499 consecutive RA patients who visited our hospital during one month were reviewed. OP was diagnosed by pathological findings by trans-bronchial biopsy or by clinical features (typical computed tomography findings, no causative agents, good response to glucocorticoids, and lack of response to antibiotics).Among 499 patients, OP was found in 19 patients and the estimated prevalence was 1.9-4.8%. No differences in clinical features were noted between the OP and non-OP groups. The mean age of OP development was 57.2 years and the period from the onset of RA to OP ranged from -4 to +34 years. Although 14 patients presented OP after the onset of RA, two developed OP before RA and three developed OP simultaneously with RA. Patients receiving tumor necrosis factor inhibitors also developed OP. RA disease activity just before onset of OP was low in 8 of 14 RA cases. At the onset of OP, only two patients showed exacerbations of arthritis, whereas most patients presented with fever and serum C-reactive protein (CRP) elevations. Glucocorticoids were effective for OP in all patients who received them. Relapse occurred in 4 of 19 cases.OP develops in approximately 4% of RA patients, which occurs independently from arthritis activity and at any time in RA patients.

Background:Interstitial lung disease (ILD), frequent lung involvement, determine the prognosis of patients with RA. The presence of ILD also influences the selection of RA therapy. However, it is not fully elucidated what groups of RA-ILD patients worsen ILD.Objectives:To identify the risk factors for worsening of ILD in RA patients under biological DMARD (bDAMARDs) therapy; particularly to determine whether types of bDMARDs are associated with exacerbation of ILD.Methods:A retrospective cohort study was conducted. Subjects were consecutive 91 RA-ILD patients who received HR-CT examination at starting and during bDMARDs therapy. Clinical data were collected by reviewing.ILD was diagnosed, when patients showed ground-glass opacity (GGO), consolidation, reticular pattern or honeycomb; the former two were acute and the latter two were chronic ILD lesions. The extent of each lesion was scored and recorded. When the score was increased, the lesion was judged as worsened. The incidence of exacerbation of ILD under an indicated agent was calculated as follows; the sum of (exposure period of the agent/exposure period of any agent) in patients with the exacerbation was divided by total exposure period of the agent.Results:Subjects were 36 males and 55 females with a mean age of 66.8 years. At the entry, GGO, consolidation, reticular and honeycomb were found in16, 20, 63 and 17, respectively. Acute and chronic ILD were observed in 34 and 68, respectively. ILD worsened in 35 (38.5%). Between patients with and without ILD exacerbation, no differences were found in demographics (sex, age, disease duration, the positivity for anti-CCP ab and RF) and radiographic findings of pulmonary abnormalities. Disease activities at as 1st and sequential CT examinations were similar in both groups.The incidences of the worsening of ILD varied according to bDMARDs (Fig 1). The incidence of total ILD worsening was high in TCZ compared to TNF and ABT. The incidence of acute ILD worsening was similar among the three groups. However, the worsening of chronic ILD was more frequently found in TCZ than other bDMARDs. The incidence of death by respiratory failure was similar in TNF, ABT, and TCZ (Fig. 2).Fig. 1Conclusion:TCZ might be a risk factor for exacerbation of ILD, particularly of chronic ILD.Fig. 2Disclosure of Interests:None declared

Background Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects joints and various organs. The lung is one of the most common site of extra-articular involvement. Interstitial lung disease (ILD) is one form of the lung involvement and influences prognosis of the patients. RA-ILD frequently developed acute exacerbation. Once acute exacerbation occurs, the prognosis of patients is poor. However, it is not fully elucidated what the risk factors for severe exacerbation of ILD are. Objectives The purpose of thisstudy was to identify the risk factors for severe exacerbation of ILD in RApatients during bDMARDs therapy.The purpose of this study was to identify therisk factors for exacerbation of ILD in RA patients under the bDMARDs therapy. Methods A retrospective cohort study. Subjects were consecutive 208 RA patients who were treated with bDMARDs from 2004 to 2015 in our department and received HRCT scan before and during the therapy. Based on HR-CT imaging, pulmonary abnormalities were classified into 4 categories (ILD, nodular lesions, airway disease (AD) and others) and 20 lesions such as ground-glass opacity (GGO), reticular pattern, bronchiolitis and bronchiectasis. We recorded their existence and distribution before andduring the therapy and examined their changes. Severe exacerbation of ILD was judged when patients revealed newly emerging/worsening of ILD lesions regardless of pre-existing pulmonary lesions and deceased or had to stop bDMARDs due to exacerbation of ILD. To identify risk factors, logistic regression analysis was conducted. Results Subjects were 208 RApatients, M/F; 64/144, mean age; 59.2 years old, disease duration; 7.9 years positive for RF in 84.1%. bDMARDs used for the longest period were TNFinhibitors in 79.8% of the subjects, abatacept in 15.4% and tocilizmab in 4.8%. Pulmonary abnormalities were found in 146 (70.2%) of RA patients before bDMARDs (ILD 81,(38.9%); nodular lesions 45, (21.6%); and ADs, 115, (55.3%)). GGO, consolidation, reticular pattern and honey combing was found in 14.8%, 19.8%, 51.9%, and 17.3% of ILD patients. Most of ILD lesions coexisted with ADs. During the observation period (3.26±2.61 years), newly emerging/worsening pulmonary lesions were found in 42.3% of patients and the incidence of which was 13.7/100person year. The incidence of newly development and worsening of ILD were 7.0/100 person years and 1.5/100 person years, respectively. Severe exacerbation of ILD was developed in 13 patients (6.3%) and the incidence of which was 2.0/100 person year. Of 13 patients, 9 died of respiratory failure. All patients with severe exacerbation revealed GGO/consolidation.Interestingly, all these active ILD lesions were newly emerging lesions, however, most of the patients had pre-existing pulmonary lesions. We identified risk factors for severe exacerbation of ILD (Table1). The risk factors for severe exacerbation of ILD were older age and pre-existing pulmonary lesions of ILD and of ADs, particularly reticular pattern, honeycomb and bronchiectasis. Sero-positivity and choice of biologics were not identified as risk factors. Conclusions The incidence of severe exacerbation of ILD was 2.0/100 person years. The risk factors forsevere exacerbation of ILD were older age and pre-existing reticular pattern,honeycomb and bronchiectasis. Disclosure of Interest: None declared

Background Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects joints and various organs including the lung. The pulmonary involvement is critical for prognosis of the patients and decision of the treatment. Moreover, the pulmonary involvement showed various abnormalities such as interstitial pneumonia (ILD) and airway disease (AD). Importantly, a pulmonary abnormality coexists with other ones in RA patients. There have been large numbers of studies on the prevalence of pulmonary abnormalities and clinical features of patients with these lesions. However, it remains to be elucidated what existence pattern of pulmonary abnormalities RA patients have. Objectives To reveal the existence pattern of the pulmonary abnormalities in RA patients using cluster analysis, and to clarify the clinical features of patients with multiple pulmonary abnormalities. Methods Subjects were consecutive 208 RA patients who were treated with bDMARDs as the first one from Feb. 2004 to Sep. 2015 in our department and received HRCT scan before and after the therapy. Pulmonary abnormalities were classified into 4 categories (ILD, nodular lesions, AD and other) and 20 lesions such as ground-glass opacity, reticular pattern, bronchiolitis and bronchiectasis and were examined their existence and distribution. Cluster analysis was conducted according to the existence of the lesions by Ward method. Clinical features were analyzed through reviewing medical records. Results Subjects were 208 RA cases (M/F; 64/144, mean age 59.2 year-old, disease duration 13.1 years). Pulmonary lesions were found in 146 (70.2%) of RA patients before treatment Imaging findings were 81of ILD (39%),45 of nodular lesion (21.6%) and 115 of AD (55%). Cluster analysis showed 6 clustered (Fig.), 1; no pulmonary lesions, 2; AD without bronchoectasia, 3; AD with bronchoectasia, 4; AD with curved linear opacities, 5; AD with nodular lesions, and 6; reticular pattern with AD. AD was common abnormalities and coexisted with other pulmonary lesions in RA. AD was found in 79%, 78% and 71% of patients with pulmonary abnormalities, ILD and nodular lesions, respectively. AD alone, AD with ILD, and AD with nodular pattern were found in 16.3%, 8.6% and 28.9%, respectively, while patients without pulmonary lesions were 29.8% in RA. AD was frequently associated with ILD and nodule compare to non-AD. No differences were found in gender, smoking history, disease duration and disease activity between patients with and without AD. New emergence or exacerbation of pulmonary abnormalities developed in AD patients compared to those without pulmonary abnormalities or AD. No significant differences were found in clinical features, among AD alone, AD with ILD and AD with nodules. Conclusions Pulmonary abnormalities were found in 70% in RA. AD was found in 55% of RA patients and coexisted with other pulmonary lesions such as ILD and nodular lesions. Patients with AD frequently showed newly emerging or worsening pulmonary lesions, regardless of the coexistence of other pulmonary lesions. Thus, AD is shared and critical pulmonary abnormality in RA. Disclosure of Interest None declared

A 26-year-old Japanese woman developed autoimmune pulmonary alveolar proteinosis (PAP) during glucocorticoid therapy for systemic lupus erythematosus (SLE). Intensive immunosuppressive therapy worsened the PAP. De-escalation of immunosuppressive therapy improved the PAP. Autoimmune PAP is rarely associated with systemic autoimmune diseases, and the present case is the first case of autoimmune PAP associated with SLE. Moreover, the present case suggests that immunosuppressive therapy should be avoided or used carefully for the treatment of patients with anti-GM-CSF antibody, such as those with autoimmune PAP.

雇用の分野における男女の均等な機会及び待遇の確保のために,「男女雇用機会均等法」が成立し,妊娠や出産を理由として職場で不利益な取り扱いをすることは禁じられている1).さらに,「男女共同参画社会基本法」が施行され,2006 年には日本医師会に男女共同参画委員会が設立している2).しかし,我が国の女性医師の就労に影響を与える因子を検討した先行研究によると,性差による就労上の不利益を経験した女性医師が多く,就労格差を女性医師は強く認識しているという結論となっている3).このことは日本ばかりではなく,海外でも同様に報告されている4,5).特に,女性医師は男性医師に比較して,非常勤パートタイムで勤務することが多いと報告されている3,4).パートタイムで働く主たる理由は,出産と子育てである5).多くの女性医師が子育てを優先するために仕方なくパートタイム勤務を選択していることは事実である.また,母性を優先させる選択は職場での昇進・キャリアアップを閉ざすという結果につながる 3).しかし,一方で女性にとって出産や育児は非常に大切な母性の獲得であり,出産を経験した女性医師は医師を職業として選択したことにより満足していると報告されている6).これが女性医師にとってのワーク・ライフ・バランスのジレンマになっている.さらに,現在,医師を養成する大学医学部では,男女は平等に入学できるが,過酷な労働を強いられる大学病院では,女性医師は常勤勤務から離職せざるを得なくなるというアンバランスが生じている.本研究は,本学の女性医師支援のあり方を考える予備的研究として,本学同窓会会員の現況報告を検討し,さらに女性医師支援に関する先行文献を考察することを目的とした.

Trimethoprim-sulphamethoxazole (TMP-STX), an agent used for prophylaxis against pneumocystis pneumonia (PCP) in immunocompromised hosts, causes serious adverse effects (AEs) in some patients. The objective of this study was to identify the risk factors for AEs caused by TMP-STX in connective tissue disease (CTD) patients and to describe the clinical features of the AEs.The medical records of 539 patients (CTDs 312, pulmonary diseases 227) receiving TMP-STX for prophylaxis against PCP were reviewed retrospectively. Patients with human immunodeficiency virus were excluded. Univariate and multivariate analyses were conducted to identify the risk factors.Adverse events caused by TMP-STX occurred in 22 of 312 (7.05 %) CTD patients, while only six of 227 (2.64 %) pulmonary disease patients developed AEs. The incidence of AEs was significantly higher in systemic lupus erythematosus (SLE) (11.0 %) and mixed connective tissue disease (MCTD) (33.3 %) patients than in other CTD patients. AEs occurred in 25 % of patients with anti-RNP antibody. Univariate analysis revealed that SLE, MCTD, and anti-RNP antibody were risk factors for AEs in CTD patients. Further multivariate analyses demonstrated that only anti-RNP antibody positivity was a risk factor for AEs. Systemic inflammation, including fever, was a characteristic manifestation of the AEs in CTD patients, particularly those with anti-RNP antibody.Positivity for anti-RNP antibody is a risk factor for AEs caused by TMP-STX in CTD patients. Systemic inflammation, including fever, might be a characteristic feature of the AEs in CTD patients, particularly those with anti-RNP antibody.

A 58-year old Japanese woman who had been diagnosed with and managed for systemic sclerosis (SSc) with pulmonary arterial hypertension died suddenly. However, the autopsy revealed marked right ventricular dilatation, and the myocardium had been replaced by fatty tissue. These findings were consistent with arrhythmogenic right ventricular dysplasia (ARVD). A literature search identified nine cases of SSc with ARVD in Japan, including this case; this number is significantly higher than the value estimated from the prevalences of ARVD and SSc in Japan, suggesting an association between these two rare diseases.

Benign metastasizing leiomyoma (BML) is a very rare disease, and although it was reported as early as1939 to result from metastasis of benign uterine myoma to the lungs and lymph nodes, its pathology remainsobscure. Here, we describe a case of pulmonary BML occurring after uterine myomectomy in a42-year-old woman. She presented with a 2-week history of dry cough on exertion. Chest radiography andcomputed tomography( CT) revealed bilateral multiple nodular lesions. The patient had a history of uterinemyoma and previously underwent myomectomy. For definitive diagnosis, lung biopsy was performed byvideo associated thoracoscopic surgery. Histopathologic examination of biopsy specimens revealed pulmonaryBML occurring after uterine myomectomy. For treatment of the pulmonary BML, gonadotropin-releasinghormone was initially administered, and 1 month later the patient underwent complete hysterectomyand bilateral salpingo-oophorectomy. Chest CT 6 months after surgery showed that the size and number oflung multiple nodular lesions did not increase compared with those before surgery. In future studies, we aimto investigate a larger number of pulmonary BML cases, as well as establish specific treatments and investigatethe prognosis of the disease.Abbreviations:BML:benign metastasizing leiomyomaSS:Sjögren's syndromeCT:computed tomographyH&E:hematoxylin and eosinVATS:video associated thoracoscopic surgeryCA:carbohydrate antigenIg:immunoguloblina SMA:a smooth muscle actin

獨協医科大学病院呼吸器・アレルギー内科を受診したHIV感染者を解析し,わが国および栃木県のHIV 感染者との比較検討を行った.対象は,2002年7月より2009年6月までの間,当科に受診歴のある34名(男27名,女7名,日本人29名,外国人5名),平均年齢は44.2歳(29歳〜67歳).男性の感染理由は,異性間(風俗,不特定)40.7%,同性間37.0%,女性はパートナーからの感染が57.1 %であった.64.7%がAIDS 発症によりHIV感染が判明し,HIV感染判明時の精査では79.4%がAIDSを発症しており,全症例の55.9%にニューモシスチス肺炎の合併を認めた.治療開始が推奨されているCD4陽性細胞低値(350/m l以下)は,97.1%の症例に認めた.以上の結果より,感染理由や年齢層については,全国の平均と同様な傾向を認めた.全国的には,HIV感染判明者の約7割がAIDS 発病前のキャリアの状態でHIV 感染が判明し,栃木県でも同様の傾向である.しかし,当科では大多数がAIDS 発症後およびAIDS 発症直前の低免疫状態でHIV 感染が判明しており,早期発見および早期介入が課題と考えられた., To be clear the clinical characteristics in Tochigi, we analyzedpatients with HIV infection in our department. Patientswith HIV infection between July 2002 and June 2009were 34 subjects (Man:Woman=27:7, Japanese:Foreigner=29:5), and mean age was 44.2 years old. In reasonof HIV infection for men, men who were infected by sexualintercourse with indefinite women were 40.7 % and menwho were infected by sexual intercourse with men were37.0 %. Women who were infected by their partners were57.1 %. 64.7 % of patients were recognized HIV infection byshowing AIDS. 79.4% of patients already had complicationsindicating AIDS, when they came to our hospital, and 55.9% of patients had pneumocystis jiroveci pneumonia. In 97.1% of patients, the number of CD4 positive cells were under350/m l. In conclusion, around 70 % of patients were recognizedHIV infection before they become AIDS in Japan. But,a large majority of patients in our department were withbecoming AIDS or just before AIDS. We need to developthe system of early intervention for HIV infection.

Recently, immunoglobulin (Ig) G4-related diseases such as autoimmune pancreatitis (AIP), sclerosingsialadenitis, retroperitoneal fibrosis, and sclerosing cholangitis have been reported. IgG4-related diseases arecharacterized by high serum IgG4 concentrations, sclerosing inflammation with numerous IgG4-positiveplasma cells, and steroid sensitivity, irrespective of their organ of origin. We describe a case of inflammatorylung disease and retroperitoneal fibrosis, suggested to involve IgG4. The patient was a 76-year-old man. Acomputed tomographic scan of the chest showed nodular air-space consolidation in the left upper lobe. Theserum IgG4 concentration was abnormally elevated, but there was no evidence of AIP. Bilateral hydronephrosisassociated with thickened soft tissue around the abdominal aorta had been diagnosed previously. Hehad undergone surgery, and retroperitoneal fibrosis was diagnosed histologically (hematoxylin and eosinstain). Histological examination of bronchoscopic specimens taken from the left S3 region showed mononuclear-cell infiltration of the fibrotic bronchial wall, including many IgG4-positive plasma cells. Specimens ofthe region affected by retroperitoneal fibrosis were retrospectively reanalyzed, and the cells were positivefor IgG4 on immunostaining, similar to the lung tissue. The patient responded to treatment with corticosteroids.In conclusion, the present case shared many clinical and clinicopathological similarities with systemicIgG4-related autoimmune disease. To our knowledge, however, this is the first reported case of inflammatorylung disease with retroperitoneal fibrosis in a patient with systemic IgG4-related autoimmune disease.

We report the case of a patient with systemic lupus erythematosus (SLE) who first revealed hemophagocytic syndrome (HPS), which was treated successfully with glucocorticoid and intravenous cyclophosphamide. The patient then demonstrated refractory thrombotic thrombocytopenic purpura (TTP) with normal a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-13 activity that responded well to rituximab. After rituximab treatment, the patient showed a flare of HPS that was controlled by additional intravenous cyclophosphamide treatment. This case showed that TTP with normal ADAMTS-13 activity is B-cell dependent and indicated that B-cell depletion might exacerbate some autoimmune conditions in SLE.

To determine the background features of peripheral nervous system (PNS) involvement in cases of primary Sjögren's syndrome (SS), we studied the nervous system involvement, mainly that of PNS, in patients with primary SS who were admitted to our hospital during a period of 19 years. Nine of 82 admitted patients with primary SS had PNS involvement and 12 had central nervous system (CNS) involvement. Among 182 secondary SS patients, 25 had CNS involvement, and none had PNS involvement. The nine patients with PNS involvement were older and their disease duration was shorter than those with CNS involvement and either primary or secondary SS. Four patients exhibiting active progression of PNS involvement had concomitant vasculopathy clinically that was confirmed by nerve or skin biopsy examination, with an increase in the serum C-reactive protein level. According to the literature, among 17 reported SS patients with PNS involvement, 13 had primary SS, and 13 had vasculitis as confirmed by biopsy examination. Nervous system involvement in cases of SS is not rare. PNS involvement was observed mostly in elderly patients with primary SS, and its active progression was concomitant with vasculopathy.

Objective.To evaluate the usefulness of F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in the management of patients with inflammatory myopathy. We examined whether FDG-PET scanning detects myositis or extramuscular lesions in patients with polymyositis (PM) and dermatomyositis (DM).Methods.FDG-PET imaging was performed in 24 patients with active inflammatory myopathy (PM, 11; DM, 13). The images were read by radiologists in a blinded manner. FDG uptake into muscles was judged positive when the intensity of muscles was higher than or equal to that of the liver. As controls, FDG imaging findings of patients with a lung mass and without muscle diseases were used. To investigate associations between FDG-PET findings and clinical/laboratory findings, the patients’ medical records were reviewed retrospectively.Results.Increased FDG uptake in muscles was found in 8 of 24 (33%) patients. In 67 of 69 (97%) controls without muscle diseases, no muscle FDG uptake was detected. The sensitivity of FDG-PET to detect myositis was lower than that of electromyogram (EMG), magnetic resonance imaging, and muscle biopsy. There were no significant differences in clinical manifestations between patients with and without increased FDG uptake in muscles, although patients with FDG muscle uptake had a tendency to have extended myositis with endomysial cell infiltration. FDG-PET detected neoplasms in patients with associated malignancy. FDG uptake in lungs was found in 7 of 18 patients with interstitial lung disease.Conclusion.FDG-PET imaging has limited usefulness for the evaluation of myositis in patients with PM/DM because of its low sensitivity, although it might be useful for detection of malignancy in these patients.

The aim of this study is to determine whether serum KL-6 and surfactant protein D (SP-D) levels predict the prognosis of patients with interstitial pneumonia (IP) in cases of polymyositis (PM) and dermatomyositis (DM).Fifty consecutive patients with PM (n = 17) or DM (n = 33) and active IP, 6 of whom died of respiratory failure, were enrolled in this study. Serum KL-6 and SP-D levels were measured every 2-4 weeks. Medical records were reviewed retrospectively. Univariate analyses and multivariate analyses with a logistic regression model were conducted.Serum KL-6 and SP-D levels were elevated in patients with active IP. At the time of diagnosis of active IP, the serum KL-6 level was within the normal range in 28 % of patients and the SP-D level was within the normal range in 46 % of patients. Serum KL-6 level increased up to 3 months after starting treatment and then decreased gradually to baseline, whereas SP-D level peaked within the first 4 weeks after treatment and decreased rapidly to normal levels. Patients with poor prognosis showed increases in KL-6 and SP-D levels during the first 4 weeks after treatment, which was confirmed by uni- and multivariate analyses. Comparing the marker levels at 2-4 weeks after treatment with those at 0 weeks, an increase in the ratio over 1.70 for KL-6 and over 1.75 for SP-D, and an increase in KL-6 over 850 U/ml during the first 4 weeks after treatment, were poor prognostic factors.Increases in serum KL-6 and SP-D levels during the first 4 weeks after starting therapy, but not their levels at any one time point, predict poor prognosis in patients with PM/DM. When marked increases of KL-6 and SP-D levels during the first 4 weeks are found or are predicted by serial measurement of the markers, patients have risks of poor prognosis and additional therapy should be considered.

Reactivation of cytomegalovirus (CMV) occurs during intensive immunosuppressive therapies. However, the influence of CMV reactivation on prognosis in patients with immunosuppressive therapies for collagen-vascular diseases (CVD) is not fully understood. To determine whether CMV reactivation affects the prognosis of patients with CVD and to identify risk factors of CMV reactivation, we reviewed, retrospectively, the medical records of 109 CVD patients who were treated with glucocorticoid (prednisolone ≥20 mg/day) and were tested for CMV antigen (CMV-Ag). CMV-Ag was detected in 34 of the 109 patients. First-time CMV-Ag detection was within 50 days from the start of intensive immunosuppressive therapy in 82% of the patients. Common manifestations at first-time CMV-Ag detection were fever, arthralgia, and rash, although 52.9% of the patients were asymptomatic. The risk factors for CMV reactivation were old age (65 years) and high-dose glucocorticoids (PSL ≥50 mg). During the 4-year study period, 18% of patients with positive CMV-Ag and 5% of those without CMV-Ag died. Patients with CMV-Ag (max CMV number ≥5/10(5) WBC) had a significantly poorer prognosis. Multivariate analysis confirmed CMV reactivation as an independent poor prognostic factor in CVD patients. Causes of death were exacerbation of pre-existing interstitial pneumonia and infection other than CMV. Our results demonstrate that CMV reactivation, particularly with a high CMV-Ag number, is a poor prognostic factor in CVD patients. Patients with older age and high-dose glucocorticoids have a high risk of CMV reactivation.

Autoantibody against platelet-derived growth factor receptors (PDGFRs) has been reported in scleroderma (SSc). However, it remains unknown whether anti-PDGFRs antibody exists in collagen vascular diseases other than SSc. To answer the question, we developed an ELISA system and examined sera from patients with SLE (n = 75), SSc (n = 31), RA (n = 25) and control individuals. We also reviewed medical records to clarify clinical features of patients with anti-PDGFRα antibody. To examine the functions of anti-PDGFRα antibody in patients, fibroblasts were cultured and stimulated in the presence of purified IgG from patients, and their cell numbers were counted. Anti-PDGFRα antibody was detected in 29% of patients with SLE and in 21% of patients with SSc. Anti-PDGFRα antibody was found in 36% with active SLE, but in 10% in an inactive phase. Immunosuppressive therapy decreased the titer of the antibody. Patients with anti-PDGFRα antibody frequently developed a rash and hematological abnormalities, particular hemolytic anemia. Moreover, anti-PDGFRα antibody in SLE failed to demonstrate agonistic or antagonistic activities on PDGFR signaling. These findings indicate that nonfunctional anti-PDGFRα autoantibody exists in patients with SLE as well as those with scleroderma, and that the antibody could be a marker of disease activity and may be a marker of a subgroup of SLE.

Background Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important hematopoietic growth factor, particularly for differentiation of alveolar macrophage, and immune modulator including inflammation. Neutralizing autoantibodies against GM-CSF antibodies cause pulmonary alveolar proteinosis (PAP). We have previously reported a SLE patient with anti-GM-CSF antibody (Ab) and PAP (Lupus 2013;22, 1060). However, it remains unknown whether there exist autoantibodies against GM-CSF in connective tissue disease (CTD) patients without PAP. Objectives To determine whether anti-GMF autoantibody is detected in sera from CTD patients. If so, to determine whether the antibody has neutralizing activity and to clarify the clinical features of patients with the antibody. Methods Subjects were 245 CTD patients (SLE; 63, DM/PM; 49, RA; 106, vasculitis; 27) and 34 healthy controls. A EIA system to detect anti-GM-CSF Abs was developed; GM-CSF was coated on the plate that was then blocked with BSA, diluted serum with PBS was added, and after washing the Ab was detected by anti-IgG Ab. To avoid non-specific binding, the optic density (OD) of the Ab was calculated as follows; OD (GM-CSF coated well) -OD (GM-CSF negative well). The neutralizing activity of the Ab was examined through inhibition of CD11b expression on neutrophils by GM-CSF; neutrophils were incubated in media with GM-CSF (5ng/ml) and serum from the subjects, and CD11b expression was examined using flowcytometry. Association of clinical features with the Ab was assessed by reviewing medical records. Results Anti-GM-CSF Ab was detected in 60% of CTD (frequencies of positivity: SLE; 70%, DM/PM; 57%, RA; 57%, vasculitis 55%) (Fig.1). PAP was not found in all cases except one SLE that has been reported previously. Neutralizing activity was not detected except the case of SLE with PAP. Pulmonary involvements including interstitial lung disease, bronchial disease and pleuritis was frequently found in RA patients positive for the Abs compared to negative patients (positive 47%, vs negative 18%; p Conclusions Non-neutralising Autoantibody against GM-CSF was frequently detected in CTD patients, particularly those with pulmonary involvements. These findings suggest that the autoantibody, which might work as carrier protein of GM-CSF, plays roles in the development of CTDs, especially pulmonary involvements in RA and SLE. Disclosure of Interest None declared

The characteristics of Pneumocystis carinii pneumonia (PCP) in patients with connective tissue diseases (CTDs) were examined retrospectively. Nine patients were enrolled in this study. Their mean age was 57.1 years. All the patients received a high-dose steroid or immunosuppressant. The onset (mean 6.6 days) of fever, cough, breathlessness, and geographical ground-glass opacities revealed by chest computed tomography was acute. The serum beta-D: -glucan level increased with a simultaneous increase in the Krebs von den Lungen (KL)-6 or surfactant protein D level. The serum immunoglobulin G (IgG) and albumin levels and the peripheral blood lymphocyte count at the onset of PCP were low, but only the serum IgG level decreased significantly. The patients were treated with trimethoprim-sulfamethoxazole or pentamidine isetionate. Six patients died eventually: two patients of progressive respiratory failure, two probably due to a recurrence of the PCP, and two with microbial respiratory infections other than PCP. Five of the six patients required mechanical ventilation. Three patients received secondary prophylaxis and survived. In conclusion, the acute onset was characteristic of PCP in patients with CTDs. High-dose steroids, immunosuppressants, and hypogammaglobulinemia are risk factors; and respiratory failure requiring mechanical ventilation, severe secondary infections, and a lack of secondary prophylaxis are poor prognostic factors. Secondary prophylaxis is recommended for all of these patients.

Background Interstitial pneumonia (IP) is a serious complication associated with polymyositis (PM) and dermatomyositis (DM). Predictive factors for poor prognosis have not been fully identified. KL-6 and surfactant protein D (SP-D) are biomarkers for existence and severity of IP. Clinical usefulness of these markers in IP in PM/DM has not been fully evaluated. Objectives To identify poor prognostic factors for IP in PM/PM. and to determine whether serum KL-6/SP-D levels predict patients with IP in PM/DM. Methods Consecutive 50 PM/DM (P: 17, DM 33) patients with active IP, 6 of whom were died of respiratory failure, were enrolled in this study. Active IP was defined as IP that was judged as requiring intensive immunotherapy for IP by physicians managing patients, based on worsening dyspnea and, expanding ground glass opacities in HR-CT or decreasing PaO2. Serum KL-6 and SP-D levels were measured before treatment for IP and every 2-4 weeks after starting therapy. To find correlation between KL-6/SP-D levels and clinical feature including prognosis, medical records were reviewed retrospectively. Results Serum KL-6 and SP-D levels were elevated in patients with active IP compared to those with inactive IP or without IP. Serum KL-6 and SP-D levels at the diagnosis of active IP were within normal range in 26% and 44% of patients with active IP, respectively. KL-6 and SP-D levels at the time of diagnosis failed to predict prognosis. Serum Kl-6 levels were increased up to 3 month after starting treatment and then decreased gradually to base lines, whereas SP-D levels were at peaks within 1st 4 weeks after the treatment and decreased rapidly to normal levels. In patients with poor prognosis showed in marked increased in KL-6/SP-D levels. Comparison of clinical features between patients with poor and good prognosis showed significant difference in Kl-6 levels at 1st 4 weeks and increase of KL-6 and SP-D levels during during 1st 4 weeks, increased AaDO2 levels before treatment and existence of alveolar opacities. Multivariate logistic regression analysis showed only increase in KL-6/SP-D levels during during 1st 4 weeks as a poor prognostic factor. Cut off levels determined by ROC analysis were 1.70 and 1.75 of increase ratio of KL-6 and SP-D levels at 2-4 weeks after treatment to those at 0 week, respectively. Increase of KL-6 during 1st 4 weeks over 800U/ml was a poor prognostic factor. Conclusions Increase in serum Kl-6/SP-D levels during 1st 4 weeks after starting therapy, but not their levels at any one time point, predicts poor prognosis. When marked increased of KL-6 and SP-D levels during the 1st 4 weeks, patients have risks of poor prognosis and additional therapy should be considered. Disclosure of Interest None Declared

Background Organizing pneumonia (OP), different name: bronchiolitis obliterans with organizing pneumonia (BOOP), is a form of interstitial lung diseases characterized by presence of buds of granulation tissue in bronchiole and alveoli. Radiographic feature of OP is diffuse alveolar opacities which are similar to bacterial pneumonia and tumors. There are two types of OP; cryptogenic OP and secondary OP. Secondary OP is associated with many entities such as infection, drugs and connective tissue diseases including RA. However, clinical features of OP in patients with RA remain unclear Objectives To clarify clinical features of OP associated with RA, particularly, to determine whether the development of OP is related to disease activity of arthritis. Methods To determine prevalence of OP, we reviewed medical records of consecutive 499 RA patients who visited our hospital in Dec 2010. For analysis of clinical features of OP, we analyzed medical records of 24 RA patients with OP; 19 extracted by the above screening and additional 5 who admitted our hospital because of OP in 2011-12. OP was diagnosed by pathological findings or typical pulmonary imaging with clinical features (migration pulmonary infiltrates/ no response to antibiotics and good response to glucocorticoid). Results Among 499 RA patients, patients with history of OP were 19 (3.8%) cases, while prevalence of interstitial pneumonia and with bronchoectasia/bronchiolitis were 13.0% and 6.0%, respectively. Among 24 patients, male was8 and female was 16. Age of the onset of OP was 60.5 ± 9.6 year (mean ± sd). RA preceded OP in 16 patients (67%), while OP developed simultaneously with RA in 3 patients, and occurred before the onset of RA in 3 cases. The interval between the onset of RA and OP was 11.6 ± 12.8 years. Positivity of RF and anti-CCP antibody were found in 18/24 and 14/17, respectively. At the onset of OP, 18 patients were treated for RA, 11 and 7 of them received MTX and d TNF inhibotors, respectively. The disease activity of RA was high in 4, moderate in4, low in 9, and CR in 1 case. Only 3 patients showed exacerbation of arthritis. Respiratory symptoms and fever were found in 14 and 18 out of 24 OP patients. All patients revealed alveolar opacities, multiple lung lesions were found in half of the cases, and spontaneous resolution of the lung infiltrates was found in 9 cases. antibiotics weres ineffective for OP and glucocorticoid dramatically improved OP. Relapse of OP was found in 5 patients without exacerbation of arthritis. Conclusions OP is not a rare pulmonary complication in RA which develops in 4% in RA. OP develops in patients whose disease activity was controlled or in those treated with TNF inhibitors, successfully. These findings suggest that OP in RA might be TNF- independent and have different pathogenesis from arthritis. Disclosure of Interest None Declared

To the Editor: We thank Dr. Pipitone, et al for their interest1 in our article2. Pipitone, et al reported high sensitivity of active myositis by 18F fluorodeoxyglucose positron emission tomography (FDG-PET) imaging3 compared with that in our study, when they defined active myositis based on the ratio of standardized uptake values of proximal muscles to that of the liver. Moreover, they reported that the … Address correspondence to Dr. K. Kurasawa, 880 Kita-Kobayashi, Mibu, Tochigi 321-0293, Japan. E-mail: kurasawa{at}dokkyomed.ac.jp