Kizuku Watanabe

Detection of antisynthetase syndrome in patients with idiopathic interstitial pneumonias

OBJECTIVES Antisynthetase syndrome (ASS) is characterized by autoantibodies to aminoacyl-tRNA synthetases (anti-synthetase) and it is frequently associated with interstitial lung disease. The purpose of this study was to elucidate the prevalence and characteristics of the anti-synthetase positive subpopulation among idiopathic interstitial pneumonias (IIPs) and to clarify the importance of screening for these antibodies. METHODS A retrospective study was performed in 198 consecutive cases with IIPs. Screening for six anti-synthetase antibodies was performed in all cases. Clinical profiles of all cases were compared with reference to the presence of anti-synthetase. High-resolution computed tomography (HRCT) findings of anti-synthetase positive cases were also analyzed. RESULTS 13 cases (6.6%) were positive for anti-synthetase. Anti-EJ was most prevalent, followed by anti-PL-12. Onset ages of anti-synthetase positive cases were younger than those of anti-synthetase negative cases. Extrapulmonary features of ASS were absent in 6 anti-synthetase positive cases (46.2%). Histologically, among 5 UIP with lymphoid follicles and 11 NSIP cases, the prevalence of anti-synthetase positive cases was 8/16 (50%). On HRCT, ground glass opacity and traction bronchiectasis were the major findings in anti-synthetase positive cases, while honeycombing was absent. CONCLUSIONS Anti-synthetase positive cases were not rare among IIPs. Anti-synthetase should be screened for in IIPs, especially in pathological NSIP or UIP with lymphoid follicles. These patients should be screened for anti-synthetase even if no suggestive extrapulmonary manifestation exists.

HRCT features of interstitial lung disease in dermatomyositis with anti-CADM-140 antibody

BACKGROUND Anti-CADM-140 antibody (anti-CADM-140), also referred to as anti-melanoma differentiation-associated gene 5 (MDA5) antibody, is a myositis-specific antibody identified in the sera of patients with clinically amyopathic dermatomyositis (C-ADM) and is associated with a worse prognosis in dermatomyositis-associated interstitial lung disease (DM-ILD). We sought to determine high-resolution computed tomography (HRCT) features of DM-ILD with anti-CADM-140. METHODS Twenty-five patients newly diagnosed with DM-ILD at Kyoto University Hospital between 2005 and 2009 were retrospectively reviewed. Serum anti-CADM-140 was measured in all patients at their first visit. Chest HRCT images taken prior to treatment were classified based on the dominant findings and their distribution, and compared between patients with and without the antibody. RESULTS Of 25 DM-ILD patients, 12 were positive and 13 were negative for anti-CADM-140. HRCT patterns differed significantly between anti-CADM-140-positive and negative patients (P = 0.002). Lower consolidation or ground-glass attenuation (GGA) pattern (50.0%) and random GGA pattern (33.3%) were the predominant patterns in anti-CADM-140-positive cases, while lower reticulation pattern (69.2%) was frequently seen in anti-CADM-140-negative cases. Anti-CADM-140-positive cases were also significantly characterized by the absence of intralobular reticular opacities (0% in anti-CADM-140 (+) vs. 84.6% in anti-CADM-140 (-), P < 0.0001). CONCLUSIONS Anti-CADM-140-positive DM-ILD was characterized by lower consolidation or GGA pattern, random GGA pattern, and the absence of intralobular reticular opacities.

The Multicenter Study of a New Assay for Simultaneous Detection of Multiple Anti-Aminoacyl-tRNA Synthetases in Myositis and Interstitial Pneumonia

Objective Autoantibodies to aminoacyl-tRNA synthetases (ARSs) are useful in the diagnosis of idiopathic inflammatory myopathy (IIM) with interstitial pneumonia (IP). We developed an enzyme-linked immunosorbent assay (ELISA) system using a mixture of recombinant ARS antigens and tested its utility in a multicenter study. Methods: We prepared six recombinant ARSs: GST-Jo-1, His-PL-12, His-EJ and GST-KS expressed in Escherichia coli, and His-PL-7 and His-OJ expressed in Hi-5 cells. After confirming their antigenic activity, with the exception of His-OJ, we developed our ELISA system in which the five recombinant ARSs (without His-OJ) were mixed. Efficiency was confirmed using the sera from 526 Japanese patients with connective tissue disease (CTD) (IIM n = 250, systemic lupus erythematosus n = 91, systemic sclerosis n = 70, rheumatoid arthritis n = 75, Sjögren’s syndrome n = 27 and other diseases n = 13), 168 with idiopathic interstitial pneumonia (IIP) and 30 healthy controls collected from eight institutes. IIPs were classified into two groups; idiopathic pulmonary fibrosis (IPF) (n = 38) and non-IPF (n = 130). Results were compared with those of RNA immunoprecipitation. Results: Sensitivity and specificity of the ELISA were 97.1% and 99.8%, respectively when compared with the RNA immunoprecipitation assay. Anti-ARS antibodies were detected in 30.8% of IIM, 2.5% of non-myositis CTD, and 10.7% of IIP (5.3% of IPF and 12.3% of non-IPF). Anti-ARS-positive non-IPF patients were younger and more frequently treated with glucocorticoids and/or immunosuppressants than anti-ARS-negative patients. Conclusion: A newly established ELISA detected anti-ARS antibodies as efficiently as RNA immunoprecipitation. This system will enable easier and wider use in the detection of anti-ARS antibodies in patients with IIM and IIP.

Computed tomography analysis of airway dimensions and lung density in patients with sarcoidosis.

Background: It was previously reported that visual scores of the lung opacities were associated with lung function in patients with sarcoidosis. However, there are no reports on the evaluation of airway dimensions or lung density by computed tomography (CT) in sarcoidosis patients. Objectives: The aim of this study was to investigate whether airway dimensions and lung densities assessed by CT associate with pulmonary function in patients with sarcoidosis. Methods: CT scanning was performed in 43 sarcoidosis patients and lung densities were measured using in-house software. Means and standard deviations of lung density, kurtosis and skewness of lung density histograms were calculated. Tracheal area and airway wall area/total airway area (WA%) of the right apical bronchus were also measured. Pulmonary function tests were performed on the same day. Results: Increased standard deviation of lung density and decreased kurtosis and skewness of lung density histograms were all associated with decreased total lung capacity, vital capacity and diffusion capacity. Increased standard deviation of lung density was also associated with decreased percentages of forced expiratory volume in 1 s and peak expiratory flow (%PEF). There was a positive correlation between tracheal area corrected by body surface area and %PEF, and negative correlation between WA% and %PEF. Stepwise regression analysis showed that increased standard deviation of lung density and decreased tracheal area were independently associated with lower %PEF. Conclusions: Thus, in sarcoidosis, densitometric parameters reflect restrictive lung function impairment. In addition to parenchymal lesions, it is concluded that the luminal area of the central airways also affects PEF.

Clinical relevance of plasma prostaglandin F2α metabolite concentrations in patients with idiopathic pulmonary fibrosis.

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology with few current treatment options. Recently, we determined an important role of prostaglandin F2α (PGF2α) in pulmonary fibrosis by using a bleomycin-induced pulmonary fibrosis model and found an abundance of PGF2α in bronchoalveolar lavage fluid of IPF patients. We investigated the role of PGF2α in human IPF by assessing plasma concentrations of 15-keto-dihydro PGF2α, a stable metabolite of PGF2α. METHODS We measured plasma concentrations of 15-keto-dihydro PGF2α in 91 IPF patients and compared these values with those of controls (n = 25). We further investigated the relationships of plasma 15-keto-dihydro PGF2α concentrations with disease severity and mortality. RESULTS Plasma concentrations of 15-keto-dihydro PGF2α were significantly higher in IPF patients than controls (p<0.001). Plasma concentrations of this metabolite were significantly correlated with forced expiratory volume in 1 second (Rs [correlation coefficient] = -0.34, p = 0.004), forced vital capacity (Rs = -0.33, p = 0.005), diffusing capacity for carbon monoxide (Rs = -0.36, p = 0.003), the composite physiologic index (Rs = 0.40, p = 0.001), 6-minute walk distance (Rs = -0.24, p = 0.04) and end-exercise oxygen saturation (Rs = -0.25, p = 0.04) when patients with emphysema were excluded. Multivariate analysis using stepwise Cox proportional hazards model showed that a higher composite physiologic index (relative risk = 1.049, p = 0.002) and plasma 15-keto-dihydro PGF2α concentrations (relative risk = 1.005, p = 0.002) were independently associated with an increased risk of mortality. CONCLUSIONS We demonstrated significant associations of plasma concentrations of PGF2α metabolites with disease severity and prognosis, which support a potential pathogenic role for PGF2α in human IPF.

Validation of the japanese version of the sarcoidosis health questionnaire: A cross-sectional study

BackgroundAlthough impaired health-related quality of life (HRQOL) has been reported in patients with sarcoidosis, there is currently no sarcoidosis-specific questionnaire in Japan. The 29-item Sarcoidosis Health Questionnaire (SHQ), originally developed in the United States, is the only sarcoidosis-specific HRQOL questionnaire currently available. The primary aim of this study was to develop and validate a Japanese version of the SHQ.FindingsThe SHQ was translated into Japanese following the forward-backward procedure. The reliability and validity of the Japanese version of the SHQ were examined. One hundred twenty-two Japanese patients with biopsy-proven sarcoidosis were evaluated by the SHQ, the Medical Outcomes Study 36-item short form (SF-36), the St. Georges Respiratory Questionnaire (SGRQ), chest radiography, an electrocardiogram, laboratory blood tests, pulmonary function tests, an echocardiogram, and assessments of dyspnea and depressive symptoms. The SHQ was found to have acceptable levels of internal consistency (Cronbachs coefficient α values = 0.68 to 0.91). SHQ scores correlated significantly with scores on the SF-36 and SGRQ. The domain or total scores on the SHQ also significantly correlated with serum levels of the soluble interleukin-2 receptor, the percentage of the predicted forced vital capacity, pulmonary arterial systolic pressure, dyspnea, and depressive symptoms. Also, the SHQ scores of patients who had one or two organ systems affected by sarcoidosis were significantly different from those of patients who had three or more organ systems involvement.ConclusionsThe Japanese version of the SHQ can be used to assess the HRQOL of patients with sarcoidosis.

A CD40 single-nucleotide polymorphism affects the lymphocyte profiles in the bronchoalveolar lavage of Japanese patients with sarcoidosis

CD40 plays a critical role in adaptive immunity, and alveolar macrophages in patients with sarcoidosis express higher levels of CD40. This study investigated the association of rs1883832, a functional single-nucleotide polymorphism in the CD40 gene with susceptibility to sarcoidosis and phenotypes of sarcoidosis. Genotyping of rs1883832 in 175 Japanese patients with sarcoidosis and 150 age- and sex-matched controls revealed no significant difference between the genotypes of the patient and control groups (CC/CT/TT, 32.8/52.0/14.7% in the patients; 37.3/48.0/14.7% in the controls, P = 0.66; allele C, 59.1% in the patients, 61.3% in the controls, P = 0.57). T-cell and CD4+ cell counts in the bronchoalveolar lavage fluid were significantly higher in the TT genotype group than in the CC and CT genotype group.

Neutrophil gelatinase-associated lipocalin in idiopathic pulmonary fibrosis

To the Editor: Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kD lipocalin that is covalently bound to matrix metalloproteinase (MMP)-9 produced by neutrophils [1]. NGAL in blood or bronchoalveolar lavage fluid (BALF) may reflect neutrophilic inflammation in the lungs [2, 3], and it is highly induced in injured epithelial cells, including those in the lung [4]. Possible roles for neutrophilic inflammation and epithelial injury have been reported in idiopathic pulmonary fibrosis (IPF). Thus, we hypothesised that NGAL may be associated with the pathogenesis of IPF. To investigate the roles of NGAL in IPF, we used immunohistochemical staining for lung specimens and measured plasma and BALF NGAL levels. Our study was approved by the Ethics Committee of Kyoto University (approval No. E438), and written informed consent was obtained from all study participants. First, we immunohistochemically stained the lung tissue specimens of six IPF patients, two nonspecific interstitial pneumonia (NSIP) patients, and a control (normal area distant from the lesion of surgically diagnosed organising pneumonia) for NGAL using a conventional method [5]. We also performed sequential immunofluorescent staining for NGAL and MMP-9. Immunohistochemical staining showed that NGAL was abundantly expressed in airway epithelial cells that covered the honeycomb cysts in IPF (fig. 1a and b). Further, histologically normal bronchioles in the fibrotic lesions also exhibited abundant NGAL expression, although apparently normal alveolar walls exhibited little NGAL expression. NGAL was also expressed in macrophages, neutrophils and some alveolar epithelial cells. Figure 1– Immunohistochemical staining results for neutrophil gelatinase-associated lipocalin (NGAL) in lung specimens from: a and b) idiopathic pulmonary fibrosis (IPF) …