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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.

Background The role of anti-elastin antibody (Ab) in the lung is unclear, although they may be involved in chronic obstructive pulmonary disease (COPD). Recently, increased anti-elastin Ab levels were reported in asthma. Objective To elucidate the role of anti-elastin Ab in asthma, we created a murine asthma model. Anti-elastin Ab in the airway was neutralized by intratracheal administration of elastin peptide, and the inhibitory effects of anti-elastin Ab on airway remodeling were evaluated. Methods BALB/c mice were immunized with ovalbumin (OVA) on days 0 and 14. After immunization, the mice received booster OVA via inhalation twice per week for 9 weeks, and bronchoalveolar lavage fluid (BALF) and lung tissues were evaluated. Results In lung tissues, airway remodeling occurred after 9 weeks of OVA sensitization. Peak levels of anti-elastin Ab and eosinophils in BALF were detected after 3 weeks of OVA sensitization. Anti-elastin Ab and eosinophil levels in BALF were significantly reduced after 3 weeks by the neutralization of anti-elastin Ab. Peak transforming growth factor-β1 levels in BALF were detected at 3 weeks after OVA sensitization and were significantly reduced by the neutralization of anti-elastin Ab. Airway remodeling in lung tissues was also significantly inhibited by the neutralization of anti-elastin Ab. Conclusions In our murine asthma model, anti-elastin Ab was recruited to the airway by OVA-induced allergic inflammation. Airway remodeling was inhibited by the neutralization of anti-elastin Ab. Anti-elastin Ab may contribute to the progression of airway remodeling.

BACKGROUND It is often difficult to differentiate between asthma and chronic obstructive pulmonary disease (COPD), and useful biomarkers are needed for accurate diagnosis. OBJECTIVE We evaluated anti-elastin antibody to identify useful biomarkers for differentiating between a diagnosis of asthma and COPD. METHODS Patients with asthma (male to female ratio = 10/13; mean age, 67.3 years), COPD (16/0; 74.8 years) and controls (8/4; 72.3 years) were enrolled. Samples from sputum and serum were collected and levels of anti-elastin Ab were measured. RESULTS The levels of anti-elastin Ab in sputum were significantly higher in asthma (11.4 ± 7.16 μg/mL) than in COPD (5.82 ± 5.16 μg/mL; P < 0.01), and serum levels in asthma (67.4 ± 29.7 μg/mL) were also significantly higher than in COPD or controls (45.0 ± 12.8 μg/mL; P < 0.05, 38.6 ± 10.4 μg/mL; P < 0.01, respectively). Anti-elastin Ab in sputum showed a positive correlation with smoking in asthma (r2 = 0.218, P < 0.05). However, no significant differences were observed in the levels of anti-elastin Ab and eosinophils, asthma phenotypes, inhaled corticosteroids, or severity in patients with asthma. Elastin was strongly expressed under the airway basement membrane in asthma compared with COPD or the healthy control. CONCLUSIONS Anti-elastin Ab in sputum could be a useful biomarker for COPD and asthma in ever-smokers. In asthma, anti-elastin Ab was recruited to the airways by both airway allergic inflammation and smoking, and it may contribute to the progression of airway remodeling via autoimmune inflammation, but not emphysema, in COPD.

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

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.

Although innate immune responses are necessary for the initiation of acquired immune responses and the subsequent successful elimination of pathogens, excessive responses occasionally result in lethal endotoxic shock accompanied by a cytokine storm. B and T lymphocyte attenuator (BTLA), a coinhibitory receptor with similarities to cytotoxic T-lymphocyte antigen (CTLA)-4 and programmed death (PD)-1, is expressed in not only B and T cells but also dendritic cells (DCs) and macrophages (Mϕs). Recently, several studies have reported that BTLA-deficient (BTLA −/− ) mice show enhanced pathogen clearance compared with WT mice in early phase of infections. However, the roles of BTLA expressed on innate cells in overwhelming and uncontrolled immune responses remain unclear. Here, we found that BTLA −/− mice were highly susceptible to LPS-induced endotoxic shock. LPS-induced TNF-α and IL-12 production in DCs and Mϕs was significantly enhanced in BTLA −/− mice. BTLA −/− DCs also produced high levels of TNF-α on stimulation with Pam3CSK4 but not poly(I:C) or CpG, suggesting that BTLA functions as an inhibitory molecule on Toll-like receptor signaling at cell surface but not endosome. Moreover, BTLA −/− DCs showed enhanced MyD88- and toll/IL-1R domain-containing adaptor inducing IFN (TRIF)-dependent signaling on LPS stimulation, which is associated with impaired accumulation of Src homology 2-containing protein tyrosine phosphatase in lipid rafts. Finally, we found that an agonistic anti-BTLA antibody rescued mice from LPS-induced endotoxic shock, even if the antibody was given to mice that had developed a sign of endotoxic shock. These results suggest that BTLA directly inhibits LPS responses in DCs and Mϕs and that agonistic agents for BTLA might have therapeutic potential for LPS-induced endotoxic shock.

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.

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.

Objective B and T lymphocyte attenuator (BTLA), a coreceptor expressed on lymphocytes, was recently described as an inhibitory coreceptor that negatively regulates lymphocyte activation. The purpose of this study was to investigate the role of BTLA in the regulation of immune homeostasis and the pathogenesis of autoimmunity. Methods We examined the levels of immunoglobulins and autoantibodies to nuclear antigens and the activation status of T cells in BTLA−/− mice. We also examined histopathologic changes in the organs of BTLA−/− mice. Results We observed that BTLA−/− mice gradually developed hypergammaglobulinemia, antinuclear antibodies, anti-SSA antibodies, anti–double-stranded DNA antibodies, and an increased number of activated CD4+ T cells in the periphery with age. Lack of BTLA led to spontaneous development of autoimmune hepatitis–like disease characterized by an elevation in the level of transaminases, interface hepatitis, and spotty necrosis of the liver. BTLA−/− mice also showed inflammatory cell infiltration of multiple organs, including the salivary glands, lungs, and pancreas; these features are similar to those of Sjogren's syndrome, which is a frequent complication of autoimmune hepatitis. Furthermore, the survival rate of BTLA−/− mice was significantly reduced after the age of 7 months. Conclusion Our results indicate that BTLA plays an important role in the maintenance of immune tolerance and the prevention of autoimmune diseases.

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.

MRL/Mp-Fas (lpr) (MRL-lpr) mice develop a systemic autoimmune disease and are considered to be a good model for systemic lupus erythematosus in humans. We have recently shown that mice lacking B and T lymphocyte attenuator (BTLA), an inhibitory co-receptor expressed mainly on lymphocytes, on a 129SvEv background spontaneously develop lymphocytic infiltration in multiple organs and an autoimmune hepatitis (AIH)-like disease. In this study, we investigated the role of BTLA in the pathogenesis of autoimmune diseases in MRL-lpr mice. We found that BTLA-deficient (BTLA(-/-)) MRL-lpr/lpr mice developed severe lymphocytic infiltration in salivary glands, lungs, pancreas, kidneys and joints as compared with BTLA-sufficient (BTLA(+/+)) MRL-lpr/lpr mice. In addition, although AIH-like disease was not found in BTLA(+/+) MRL-lpr/lpr mice, AIH-like disease was exacerbated in BTLA(-/-) MRL-lpr/lpr mice as compared with that in BTLA(-/-) 129SvEv mice. These results suggest that BTLA plays a protective role in autoimmune diseases in MRL-lpr mice and that AIH-like disease develops in BTLA(-/-) mice even in the absence of Fas-dependent signaling.

Inhibitory coreceptors are thought to play important roles in maintaining immunological homeostasis, and a defect in the negative signals from inhibitory coreceptors may lead to the development of autoimmune diseases. We have recently identified B and T lymphocyte attenuator (BTLA), a new inhibitory coreceptor expressed on immune cells, and we suggest that BTLA may be involved in the development of autoimmune diseases using BTLA-deficient mice. However, the role of BTLA in the pathogenesis of autoimmune diseases in humans remains unknown. We, therefore, examined the possible association between BTLA and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) by conducting a case-control genetic association study. We found that 590C single-nucleotide polymorphism (SNP) of BTLA gene was significantly associated with susceptibility to RA, but not to SLE or SS. Furthermore, RA patients bearing this 590C SNP developed the disease significantly earlier than the patients without this allele. We also found that BTLA with 590C allele lacked the inhibitory activity on concanavalin A- and anti-CD3 Ab-induced IL-2 production in Jurkat T cells. These results suggest that BTLA is an RA-susceptibility gene and is involved in the protection from autoimmunity in humans.

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.

Although B and T lymphocyte attenuator (BTLA) was originally identified as an inhibitory coreceptor selectively expressed on Th1 cells and B cells, recent studies have revealed that BTLA is expressed on a variety of cells, including macrophages, dendritic cells, and NK cells, and modulates their functions. However, the role of BTLA in the regulation of NKT cell function remains unknown. In this study, we found that BTLA was expressed on NKT cells at the levels similar to those on T cells and that BTLA-deficient (BTLA−/−) NKT cells produced larger amounts of IL-4 and IFN-γ upon α-glactosylceramide stimulation as compared with wild-type (WT) NKT cells. In vivo, BTLA−/− mice produced larger amounts of IL-4 and IFN-γ upon Con A injection and were more susceptible to Con A-induced hepatitis than WT mice. In addition, the augmentation of Con A-induced hepatitis in BTLA−/− mice was not observed in BTLA/NKT-double deficient mice. Moreover, NKT−/− mice reconstituted with BTLA−/− NKT cells were significantly more susceptible to Con A-induced hepatitis as compared with NKT −/− mice reconstituted with WT NKT cells. These results suggest that BTLA functions as the inhibitory coreceptor of NKT cells and plays a critical role in the prevention of NKT cell-mediated liver injury.

The surface expression of BTLA and its accumulation at the immunological synapse are tightly regulated by TCR and HVEM stimulation in CD4+ T cells. BTLA, a recently cloned coreceptor expressed on lymphocytes, negatively regulates cell activation by recruiting SHP-1/SHP-2. However, the mechanisms that regulate the intracellular localization of BTLA and its trafficking to the cell surface in T cells are still unknown. To determine the mechanisms that regulate the expression of BTLA on the surface of T cells, we examined the subcellular localization of BTLA in mouse T cells in a steady state, as well as upon activation by using a confocal laser-scanning microscopy. We found that BTLA was localized mainly in the Golgi apparatus and secretory lysosomes in resting CD4+ T cells. We also found that intracellular BTLA was translocated to the cell surface and accumulated at the immunological synapse upon TCR stimulation. Furthermore, we found that the BTLA-HVEM interaction was required for the association of BTLA with lipid rafts. These results indicate that the surface expression of BTLA and its accumulation at the immunological synapse are tightly regulated by TCR and HVEM stimulation to deliver efficient inhibitory signals in the regulation of CD4+ T cell activation.

Recent studies have suggested that statins, the inhibitors for 3-hydroxy-3-methyglutaryl (HMG)-CoA reductase in the mevalonate pathway, exhibit anti-inflammatory effects. However, the immune modulatory effects of statins on the differentiation of CD4(+) T cells and their underlying mechanisms are still largely unknown. To address these issues, we examined the effect of simvastatin and inhibitors for protein farnesylation and geranylgeranylation on the differentiation of IL-17-producing T cells (T(h)17 cells) and Foxp3(+) CD4(+) T cells. Simvastatin inhibited the differentiation of T(h)17 cells through the inhibition of HMG-CoA reductase activity but enhanced the differentiation of Foxp3(+) CD4(+) T cells. Geranylgeranyltransferase I inhibitor, GGTI-298, but not farnesyltransferase inhibitor, FTI-277, mimicked the effects of simvastatin, indicating that the inhibition of protein geranylgeranylation is responsible for the effects. Moreover, Foxp3(+) CD4(+) T cells developed in the presence of transforming growth factor-beta and GGTI-298 functioned as regulatory T cells (Tregs) in in vitro T cell proliferation assay as well as in an autoimmune colitis model. Finally, GGTI-298 induced SOCS3 expression and inhibited IL-6-induced signal transducers and activators of transcription3 phosphorylation in CD4(+) T cells. Taken together, these results indicate that protein geranylgeranylation enhances the differentiation of T(h)17 cells and inhibits the differentiation of Foxp3(+) Tregs partly via the inhibition of SOCS3 expression.

We report 51- and 43-year-old Japanese female patients with systemic lupus erythematosus (SLE) associated with subarachnoid hemorrhage (SAH) due to rupture of intracranial saccular aneurysms. We also review the literature of Japanese SLE patients with SAH. SAH in Japanese SLE patients is more frequent than in patients from Western countries, has different features from the general population, and can occur regardless of SLE disease activity. Clinicians must pay attention to SAH in all SLE patients.

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

Background IgG4 related disease (IgG4RD) is a multi-organ affecting disease characterized by fibro-sclerosing lesions with IgG4+ cell infiltration. Serum IgG4 elevation is a critical clue for diagnosis of IgG4RD. However, there are patients of non-IgG4RDs whose IgG4 levels are elevated. Clinical features of these patients have not been fully elucidated. Objectives To clarify clinical features of patients with serumIgG4 elevation, particularly, to determine whether IgG4 RD is a distinctive disease in patients with IgG4 elevation and whether there is a subset of non-IgG4RDs which have strong similarity to IgG4RD. Methods For determination of the prevalence of patients with serum IgG4 elevation, consecutive 185 patients who admitted our department during 2 months were enrolled. For clarification of clinical features of patients with IgG4 elevation (IgG4>135mg/dl), 68 cases with IgG4 elevation were selected from consecutive 350 patients receiving IgG4 test in clinical practice at our hospital and their medical records were reviewed retrospectively. IgG4RD was diagnosed by comprehensive diagnostic criteria for IgG4-related disease (Mod Rheumatol.22:21-30; 2012). Cluster analysis according to organ involvements was performed through Ward9s method. Results Prevalence of serum IgG4 elevation in general inpatients was 9/1850 (4.9%). Only 1 of 9 was IgG4RD. Among 68 cases with IgG4 elevation who received IgG4 test in clinical practice, IgG4RD was 41%. Cluster analysis according to organ involvements revealed 5 clusters; cluster1: multiple sclerosing lesions with salivary, orbital and retroperitoneal lesions, 2: sclerosing lesions with autoimmune pancreatitis, 3: pulmonary inflammation, 4 varieties of inflammatory diseases including connective tissue diseases, and 5: pleuritis. Cluster 1 and 2 were divided from other ones at 1st node. IgG4RD existed only cluster 1 and 2. In addition to sclerosing lesions, non-sclerosing lesions were found in 13% of cluster 1, 43% of cluster 2, 33% of IgG4RD and 70% of non-IgG4RDs. Non-sclerosing lesions were developed as organ limited inflammation in most cases of IgG4RD and non-IgG4RDs, which was contrast to sclerosing lesions in IgG4RD affecting multi-organs. Among non-sclerosing lesions, IgG4+ cells were observed. Pathological examination of non-sclerosing lesions revealed IgG4+ cell inflammation in 4/5 in IgG4RD and 8/21 in I non-IgG4RDs. The lesions in non-IgG4RDs were indistinguishable from those in IgG4RD. Patients of non-IgG4RDs with IgG4+ cells had similar clinical features to IgG4RD including high IgG4 levels, low CRP levels and good response to glucocorticoid in addition to pathological findings. Conclusions IgG4RD is a minor, but a distinctive disease in patients with serum IgG4elevation, characterized by sclerosing lesions affecting multiple organs. IgG4RD causes non-sclerosing lesions with IgG4+ cells as well as sclerosing ones. Among non-IgG4RDs, there are patients with IgG4 + non-sclerosing lesions indistinguishable from those of IgG4RD and they had similar clinical features to IgG4RD. It might be necessary to provide a position to these cases in “the extended spectrum of IgG4RD” defined as having IgG4+ cell inflammation and serum IgG4 elevation. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4032

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