Hanbo Yang

Factors Predicting Malignancy in Patients with Polymyositis and Dermatomyostis: A Systematic Review and Meta-Analysis

Objective To define potential factors that could predict concomitant neoplastic diseases in patients diagnosed with PM/DM, which could inform screening decisions. Methods Two researchers independently reviewed articles from Pubmed (MEDLINE), EMBASE, Cochrane Plus Library and ISI Web of Knowledge with no restrictions on study design or language. Given that some of the studies combined PM and DM patients as research subjects while others included only DM patients, data were subjected to meta-analyses for all combined PM/DM studies and studies that included only DM patients to obtain informative results. Results For PM/DM patients, the following factors are all associated with an increased risk of malignancy: older age, age greater than 45, male sex, dysphagia, cutaneous necrosis, cutaneous vasculitis, rapid onset of myostis (<4 weeks), elevated CK, higher ESR, higher CRP levels. Several factors were associated with lower-than-average risk, including the presence of ILD, arthritis/arthralgia, Raynauds syndrome, or anti-Jo-1 antibody. For DM patients, results indicated an increased risk of malignancy with older age, male sex, the presence of cutaneous necrosis, elevated ESR (>35 mm/hr), higher CRP levels, or anti-p155 antibody. In addition, the presence of anti-ENA antibodies seem to be related to reduced risk of malignancy. Conclusion Awareness and implementation of early-stage cancer screening in PM/DM patients who have these identified factors – such as being older than 45, male sex, cutaneous necrosis, cutaneous vasculitis – are of crucial importance from public health and clinical perspectives and provide insight into the etiopathogenesis of CAM.

Elevated Serum Levels of Soluble CD163 in Polymyositis and Dermatomyositis: Associated with Macrophage Infiltration in Muscle Tissue

Objective. To investigate serum levels of soluble CD163 (sCD163) in patients with polymyositis (PM) and dermatomyositis (DM), and to correlate these to clinical manifestations and laboratory data. Methods. Serum levels of sCD163 were detected in 24 patients with PM, 84 patients with DM, and 46 healthy controls by using the ELISA method. Immunohistochemistry staining of macrophage infiltration in muscle tissue using anti-CD163 monoclonal antibody was conducted on muscle biopsy specimens from 13 patients with PM and 17 with DM. Results. Serum levels of sCD163 were significantly increased in patients compared with healthy controls (p < 0.001). Patients with interstitial lung disease (ILD) had statistically higher sCD163 levels than patients without ILD (p < 0.001). High serum sCD163 levels were associated with increased incidence of antinuclear antibody (p < 0.05), higher serum levels of immunoglobulin G (p < 0.01) and immunoglobulin A (p < 0.05), and increased erythrocyte sedimentation rates (p < 0.01). Serum sCD163 levels were inversely correlated with CD3+ T cell counts in peripheral blood of patients (r = −0.306, p < 0.01). Cross-sectional assessment and longitudinal study revealed a significant correlation between serum sCD163 levels and disease activity. Patients with high serum sCD163 levels showed a higher incidence of CD163+ macrophage infiltration in muscle tissue than patients with normal sCD163 levels (chi-square value = 10.804, p < 0.01). Conclusion. Serum levels of sCD163 were significantly elevated and correlated with disease severity in patients with PM/DM, suggesting serum sCD163 as a promising biomarker in the disease evaluation of PM/DM. Our finding of elevated serum sCD163 levels associated with muscle macrophage infiltration highlights the role activated macrophage plays in the pathogenesis of PM/DM.

Clinical Profiles and Prognosis of Patients with Distinct Antisynthetase Autoantibodies

Objective. To compare the clinical characteristics and identify the longterm outcomes of Chinese patients with different antisynthetase antibodies. Methods. We investigated retrospectively 124 consecutive patients with antisynthetase syndrome. Medical records, laboratory results, and computed tomography images were obtained. Results. The antisynthetase antibodies we investigated were anti-Jo1 (n = 62), anti-PL7 (n = 31), anti-PL12 (n = 12), and anti-EJ (n = 19). The overall prevalence of interstitial lung disease (ILD) reached 94.4% among study patients. Eleven patients (8.9%) developed rapidly progressive ILD (RP-ILD). Eight patients (6.5%) experienced malignancy. RP-ILD was statistically more prevalent in patients with antisynthetase syndrome with anti-PL7 than those without anti-PL7 (p = 0.028). Anti-Ro52–positive patients with antisynthetase syndrome experienced higher frequency of RP-ILD than those without anti-Ro52 (p = 0.001). Further, anti-PL7–positive patients coexisting with anti-Ro52 exhibited more RP-ILD than those without anti-Ro52 (p = 0.001). Patients with antisynthetase syndrome with RP-ILD had a higher proportion of neutrophils in bronchoalveolar lavage fluid and serum ferritin than those without RP-ILD (p = 0.006 and p = 0.013, respectively). Although no differences were observed between the Kaplan-Meier curves of the 4 antisynthetase antibodies subgroups (p = 0.349), the survival rate of patients with anti-PL7 decreased more rapidly in the early stage of longterm followup compared with those with other antisynthetase antibodies. The presence of RP-ILD, malignancy, and elevated serum ferritin was identified to be associated with poor prognosis in patients with antisynthetase syndrome. Conclusion. Our study investigates the clinical phenotypes and outcomes of patients with antisynthetase syndrome with distinct antisynthetase antibodies and highlights the link between the anti-PL7 antibody and RP-ILD.

Increased Levels of Soluble Programmed Death Ligand 1 Associate with Malignancy in Patients with Dermatomyositis

Objective. To investigate the levels of soluble programmed death ligand 1 (sPD-L1) and evaluate its association with malignancy in patients with dermatomyositis (DM). Methods. Levels of sPD-L1 were measured in serum from 88 DM patients without malignancies (sDM), 40 with cancer-related DM (CRDM), and 30 healthy controls (HC) using ELISA. The CRDM subjects were divided into new-onset cancers (nCRDM) and stable cancers (sCRDM). Receiver-operating characteristic (ROC) curve analysis was performed to determine the cutoff sPD-L1 value that distinguished patients with nCRDM from those who were sDM. Serum antitranscriptional intermediary factor 1-γ (TIF1-γ) antibodies were detected using immunoblot, and the diagnostic values for malignancy were compared with sPD-L1 levels in patients with DM. Results. Serum sPD-L1 levels were significantly higher in sDM [median 12.3 ng/ml, interquartile range (IQR) 8.4–16.2] than in HC (median 1.3 ng/ml, IQR 0.4–2.2, p = 0.0001). Extremely high sPD-L1 levels were seen in nCRDM (median 18.5 ng/ml, IQR 13.8–22.4), much higher than those in sCRDM (median 8.5 ng/ml, IQR 6.8–11.8, p = 0.0001). The sPD-L1 levels in 4 patients with nCRDM decreased after curative cancer treatment (p = 0.013). ROC curve analysis revealed that the sPD-L1 value distinguishing nCRDM from sDM was 16.1 ng/ml, with an area under the curve value of 0.72 ± 0.04 (p = 0.0001). The combination of sPD-L1 and anti-TIF1-γ antibodies yielded greater specificity and positive predictive value in diagnosing cancer, reaching values of 95% and 70%, respectively. Conclusion. Serum sPD-L1 levels increased significantly in sDM, and markedly high sPD-L1 levels could be a diagnostic indicator for malignancies in patients with DM, especially in those with anti-TIF1-γ antibodies.

Genetic association of HLA-DRB1 multiple polymorphisms with dermatomyositis in Chinese population

Genetic variation in HLA plays an important role in the pathogenesis of dermatomyositis (DM). The aim of this study was to investigate the association of HLA class II with DM in China. Two hundred and twenty‐four DM patients and 300 healthy controls were randomly enrolled at China‐Japan Friendship Hospital. High‐resolution typing of HLA‐DRB1 alleles was performed by sequencing based typing. The HLA‐DQA1 and HLA‐DQB1 alleles were determined by polymerase chain reaction sequence‐specific primers. The frequencies of HLA‐DRB1*09:01 (28.6% vs 11.3%, P < .0001, odds ratio, OR = 3.14, 95% confidence interval, CI = 2.47‐3.99) and HLA‐DRB1*12:01 (29.0% vs 11.0%, P < .0001, OR = 3.30, 95% CI = 2.59‐4.20) in DM patients were significantly higher than that in healthy controls. No significant difference was found in HLA‐DQA1 or DQB1 alleles between DM patients and healthy controls. Furthermore, DM patients with anti‐melanoma differentiation‐associated gene 5 antibody (anti‐MDA5) had a significantly higher frequency of HLA‐DRB1*12:01 compared to that for patients without anti‐MDA5 (P < .0001, OR = 4.77, 95% CI: 2.29‐9.93). Multivariate binary logistic regression analysis was performed to identify the risk factors for interstitial lung disease. The HLA‐DRB1*09:01 allele was a poor prognostic factor (P = .01, OR = 9.21, 95% CI: 1.47‐57.50) for DM patients with anti‐MDA5 autoantibody. In summary, our findings indicate that HLA‐DRB1*09:01 and HLA‐DRB1*12:01 alleles may contribute to susceptibility of adult DM in Han Chinese population. In addition, the DRB1*12:01 genotype is significantly associated with the presence of anti‐MDA5 antibody in DM patients.

Differential clinical associations of anti‐nuclear matrix protein‐2 autoantibodies in patients with idiopathic inflammatory myopathies

To investigate the associations between anti–nuclear matrix protein 2 (anti–NXP‐2) autoantibody levels and disease activity as well as calcinosis severity in patients with idiopathic inflammatory myopathies (IIMs).

A simple method for removing low-density granulocytes to purify T lymphocytes from peripheral blood mononuclear cells

ObjectivesLow-density granulocytes (LDGs) can form neutrophil extracellular traps (NETs) spontaneously and excessively. When peripheral blood mononuclear cells (PBMCs) are used for studying T lymphocytes, LDGs contained in the PBMCs may decrease the threshold of activating T lymphocytes by forming NETs. This study focused on the profiles of LDGs in common autoimmune diseases and methods for removing LDGs from PBMCs.MethodsThe percentages of LDGs in PBMCs from 55 patients with dermatomyositis (DM), 15 with polymyositis (PM), 42 with rheumatoid arthritis (RA), 25 with systemic lupus erythematosus (SLE), and 19 healthy controls were determined by flow cytometry. Three methods of removing LDGs were explored and compared. After removal, PBMCs from six patients with positive T-SPOT.TB were tested again to find out if LDGs contained in the PBMCs could influence T lymphocyte reactions.ResultsSignificantly higher LDG percentages were found in PBMCs from patients with DM ((8.41±10.87)%, P<0.0001), PM ((8.41±10.39)%, P<0.0001), RA ((4.05±6.97)%, P=0.0249), and SLE ((7.53±11.52)%, P=0.0006), compared with the controls ((1.28±0.73)%). The T-SPOT.TB values significantly decreased after LDGs were removed. Increasing relative centrifugal force (RCF) within a limited range can decrease the LDG percentage from an initial high level, but not markedly increase the LDG clearance rate. Compared with the whole blood sediment method, the PBMC adherence method can significantly remove LDGs yet scarcely influence the T lymphocyte percentage in PBMCs.ConclusionThe LDG percentage in PBMCs is significantly increased in patients with SLE, DM, PM, and RA. The influence of LDGs on T lymphocytes cannot be ignored in PBMC cultures. The adherence method is a simple and easy-to-use method for removing LDGs and purifying T lymphocytes from PBMCs.中文概要题目一种从外周血单个核细胞中祛除低密度粒细胞并纯化T 淋巴细胞的简易方法目的系统性红斑狼疮(SLE)患者外周血单个核细胞 (PBMCs)中的低密度粒细胞(LDGs)可以自 发而过度地形成中性粒细胞胞外网状陷阱 (NETs),而形成的NETs 会降低T 细胞激活的 阈值。采用PBMCs 做淋巴细胞研究时,所含的 异常增多的LDGs 可能会显著影响实验结果。因 此需要了解其他自身免疫病中LDGs 的比例,并 需要一种简便地祛除PBMCs 中LDGs 的方法。创新点首次提出LDGs 清除的方法,验证了离心后贴壁法清除LDGs 的有效性和可靠性。方法采用流式细胞仪测定55 例皮肌炎(DM)患者、 15 例多发性肌炎(PM)患者、42 例类风湿关节 炎(RA)患者、25 例SLE 患者(阳性对照)和 19 例健康对照(阴性对照)PBMCs 中LDGs 的 比例。采用提高离心力、离心后贴壁和全血沉淀 后再离心这三种方法祛除PBMCs 中的LDGs,进 一步比较各种方法的LDGs 清除率和对PBMCs 中T 细胞的影响程度。清除T-SPOT.TB 阳性患者 PBMCs 中LDGs 后复测T-SPOT.TB,明确LDGs 是否对T-SPOT.TB 结果有影响。结论本研究中DM、PM、RA 和SLE 患者PBMCs 中 LDGs 比例普遍升高(图1)。清除PBMCs 中LDGs 后,T-SPOT.TB 显著降低(图2)。离心后贴壁 法不但能最有效地清除LDGs,且对PBMCs 中T 细胞的比例影响最小(图3~5)。综上所述,PBMCs 中LDGs 的比例在DM、PM、RA 和SLE 患者中 普遍增高;采用PBMCs 做T 细胞相关研究时 LDGs 通过形成NETs 对T 细胞激活的影响不能 忽视;离心后贴壁法可以简单而高效地清除 PBMCs 中的LDGs。