OBJECTIVE:The aim of the study was to investigate the characteristics and prognosis of patients with immune-mediated necrotizing myopathy (IMNM) based on clinical, serological and pathological classification. METHODS:A total of 138 patients with IMNM who met the 2018 European Neuromuscular Center criteria for IMNM including 62 anti-SRP, 32 anti-HMGCR-positive and 44 myositis-specific antibody-negative were involved in the study. All patients were followed up and evaluated remission and relapse. Clustering analysis based on clinical, serological and pathological parameters was used to define subgroups. RESULTS:Clustering analysis classified IMNM into three clusters. Cluster 1 patients (n = 35) had the highest creatine kinase (CK) levels, the shortest disease course, severe muscle weakness and more inflammation infiltration in muscle biopsy. Cluster 2 patients (n = 79) had the lowest CK level and moderate inflammation infiltrate. Cluster 3 patients (n = 24) had the youngest age of onset, the longest disease course and the least frequency of inflammatory infiltration. Patients in cluster 3 had the longest time-to-remission [median survival time: 61 (18.3, 103.7) vs 20.5 (16.2, 24.9) and 27 (19.6, 34.3) months] and shorter relapse-free time than those in cluster 1 and 2 [median remission time 95% CI 34 (19.9, 48.0) vs 73 (49.0, 68.7) and 73 (48.4, 97.6) months]. Patients with age of onset >55 years, more regeneration of muscle fibres, more CD4+ T infiltration and membrane attack complex deposition had more favourable outcomes regarding time to achieving remission. CONCLUSIONS:Stratification combining clinical, serological and pathological features could distinguish phenotypes and prognosis of IMNM. The pathological characteristics may impact the long-term prognosis of patients with IMNM.

Abstract Objective To investigate the association of serum anti-Jo-1 antibody levels with the disease activity and prognosis in anti-Jo-1-positive patients with antisynthetase syndrome (ASS). Methods This study included 115 anti-Jo-1-positive patients with ASS who were admitted to China-Japan Friendship Hospital between 2009 and 2019. Anti-Jo-1 antibody serum levels at initial admission and follow-up were determined by enzyme-linked immunosorbent assay (ELISA). Global and organ disease activity was assessed at baseline and follow-up according to the International Myositis Assessment and Clinical Studies guidelines. Results Among enrolled patients, 70 (60.9%) patients initially presented with interstitial lung disease (ILD), and 46 (40%) patients presented with with muscle weakness at initial admission. At baseline, patients with ILD had lower levels of anti-Jo-1 antibodies than those without ILD (p = 0.012). Baseline anti-Jo-1 antibody levels were higher in patients with muscle weakness, skin involvement, and arthritis (all p < 0.05) compared to those without these manifestations. Baseline anti-Jo-1 antibody levels were positively correlated with skin visual analogue scale (VAS) scores (r = 0.25, p = 0.006), but not with disease activity in other organs. However, changes in anti-Jo-1 antibody levels were significantly positively correlated with the changes in PGA (β = 0.002, p = 0.001), muscle (β = 0.003, p < 0.0001), and pulmonary (β = 0.002, p = 0.013) VAS scores, but not with skin and joint VAS scores. Older age of onset (hazard ratio [HR] 1.069, 95% confidence interval [CI]:1.010–1.133, p = 0.022) and higher C-reactive protein (CRP) levels (HR 1.333, 95% CI: 1.035–1.717, p = 0.026) were risk factors for death. Conclusion Anti-Jo-1 titers appear to correlate more with disease activity changes over time rather than with organ involvement at baseline, which provides better clinical guidance for assessing the disease course using anti-Jo-1 levels.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies are one of the myositis-specific antibodies which is associated with immune-mediated necrotizing myopathy (IMNM). However, the relationship between anti-HMGCR isotypes and prognosis has not yet been fully investigated. This study was conducted to gain insight into the association between anti-HMGCR isotypes and clinical, and prognosis in IMNM patients who were positive for anti-HMGCR antibodies. Levels of anti-HMGCR isotypes (IgG, IgA and IgM) were assessed by enzyme-linked immunosorbent assay (ELISA) in 123 consecutive serum samples obtained from 71 patients who were positive for anti-HMGCR IgG at baseline. Disease activity was assessed by manual muscle testing (MMT) 8, Physician’s Global Assessment (PGA) visual analog scale (VAS), and muscle VAS. Baseline anti-HMGCR IgG levels were correlated with PGA VAS (r = 0.24; p = 0.04), muscle VAS (r = 0.32; p < 0.01), and MMT8(r=-0.24; p = 0.04), and baseline anti-HMGCR IgM levels were positively correlated with PGA VAS (r = 0.27, p = 0.02), muscle VAS (r = 0.24, p = 0.04). Anti-HMGCR IgM positive patients had a lower age of onset [29(25,46) vs. 51(33,65), p = 0.006], and a higher proportion of neck weakness (63.5

Objective To investigate the association between the anti-melanoma differentiation associated gene 5 (MDA5) IgG subclasses and prognosis of patients with dermatomyositis (DM)-associated interstitial lung disease (ILD). Methods This retrospective study included 122 anti-MDA5 positive DM-ILD patients admitted from October 2017 to October 2020 as training cohort, and additional 68 patients from August 2014 to September 2017 as validation cohort. The levels of anti-MDA5 total IgG and IgG subclasses were measured using in-house enzyme-linked immunosorbent assays, and analysed in association with the patient prognosis. Results In the training cohort, the concentrations of anti-MDA5 IgG1 and IgG3 in non-survivors were significantly higher than in survivors (P < 0.05), whereas there were no significant differences in the IgG2 and IgG4 levels. Kaplan-Meier survival analysis revealed that the levels of anti-MDA5 total IgG, IgG1 and IgG3 were associated with mortality (P < 0.05). Multivariate analysis revealed anti-MDA5 IgG1 >13 U/ml and anti-MDA5 IgG3 >11 U/ml were independent risk factors for death of DM-ILD patients (P < 0.05). Anti-MDA5 IgG1 was confirmed as an independent risk factor in the validation cohort, while anti-MDA5 IgG3 was not. Anti-MDA5 IgG1 showed greater discriminable power for patient prognosis (Youden index 0.494) than anti-MDA5 total IgG, IgG3, or the combination of IgG1 and IgG3 (Youden index 0.356, 0.32 and 0.447, respectively). Conclusion Anti-MDA5 IgG1 and IgG3 are significantly associated with poor prognosis in DM-ILD patients, and anti-MDA5 IgG1 is more efficient as a prognostic biomarker in DM-ILD patients.

目的 分析特发性炎性肌病(IIM)中多发性肌炎(PM)的发生率及其特征,探讨IIM中PM是否被过度诊断.方法 纳入2008-2019年于中日友好医院风湿免疫科住院依据Bohan与Peter标准诊断的所有IIM患者.确定诊断的PM(definite PM,dPM)定义为具有典型的PM临床特征和病理特征,包括肌酸激酶(CK)升高和肌无力,肌活检呈现肌细胞膜表达MHC-I阳性和CD8+T 细胞浸润肌内膜.同时,参照IIM各亚型的最新诊断标准,排除DM、抗合成酶综合征(ASS)、免疫介导的坏死性肌病(IMNM)、散发性包涵体肌炎和其他肌病.应用SPSS 24.0进行统计学分析.Kruskal-Wallis检验和x2 检验用于比较dPM组和其他IIM亚型患者临床特点的差异.结果 共1 259例IIM纳入研究,其中1 015例(80.6％)为DM,244例(19.4％)为PM.参照严格定义的dPM标准,IIM中仅有0.5％(6/1 259)的患者可被诊断为dPM.原先诊断为PM的患者在新的IIM亚型分类中多数为IMNM和ASS,其中48.0％(117/244)为IMNM,32.0％(78/244)为ASS.6例dPM患者中女性4例,占66.7％,其中1例合并RA,1例合并SSc.所有dPM患者均有肌无力,轻度CK升高[611(391,1 451)]U/L,肌炎特异性自身抗体均为阴性.除了 1例dPM患者因合并慢性阻塞性肺疾病,未接受免疫调节治疗外,其余5例患者均予低/中等剂量糖皮质激素联合或不联合免疫抑制剂治疗.在随访(38±26)个月后,患者肌力均改善.结论 PM是一类非常罕见的IIM临床亚型,PM在临床上存在过度诊断.严格定义的PM是一类临床症状轻,预后好的疾病.

ObjectiveTo explore the role of peripheral lymphocyte count in phenotyping and prognosis prediction in dermatomyositis (DM) patients with anti-MDA5 antibodies. MethodsIn total, 1669 patients with idiopathic inflammatory myopathy (IIM) were retrospectively enrolled. Clinical characteristics and prognosis of patients with anti-MDA5+ DM were analyzed in association with peripheral lymphocyte counts and clusters determined by unsupervised machine learning. ResultsThe peripheral lymphocyte count was significantly lower in the anti-MDA5+ DM group (N = 421) than in the other IIM serotype groups. The anti-MDA5+ DM patients were divided into three groups; the severe lymphopenia group had skin ulcers and rapidly progressive interstitial lung disease (RP-ILD); patients with a normal lymphocyte count had a younger age of onset, more frequent arthritis, and normal serum ferritin levels, whereas mild lymphopenia group showed a moderate increase of serum ferritin and intermediate incidence of RP-ILD. Survival analysis revealed that the 3- and 6-month mortality rates were significantly higher in the severe lymphopenia group (29.0% and 42.1%, respectively) than in the mild lymphopenia group and normal lymphocyte count group (p value <0.001). Consistently, unsupervised machine learning identified three similar groups; the arthritis cluster shows the highest lymphocyte counts and best prognosis; the RP-ILD cluster presents the lowest peripheral lymphocyte, high incidence of RP-ILD, and poor prognosis; the typical DM rash cluster had a moderate peripheral lymphocyte count and an intermediate prognosis. ConclusionsLymphopenia is a unique manifestation of anti-MDA5+ DM. Peripheral lymphocyte count can define clinical phenotypes and predict prognosis in anti-MDA5+ DM.

8568 Background: Low dosage computer tomography (LDCT) has been widely adopted as a sensitive method to detect early-stage lung cancer; however, debate regarding its accuracy and overdiagnosis is still ongoing. An accurate non-invasive test is needed to identify malignant nodules and reduce unnecessary invasive procedures. Studies show that plasma proteins and LDCT imaging features may be used to discriminate malignant pulmonary nodules from benign ones. We aimed to develop a combinatorial approach integrating serum protein markers and imaging features to improve the classification of pulmonary nodules. Methods: This study established a prospective research cohort, which enrolled 608 patients of pulmonary nodules. Plasma samples were collected to measure protein levels using Proximity Extension Assay (PEA) technology. The imaging features of the pulmonary nodules were extracted using the python 'radiomics' package. Following feature extraction, a deep learning networks model was built using training cases. The model was then tested in the testing set to evaluate its accuracy and robustness. Results: From the study cohort, 184 benign (BN) and 184 malignant (MT) samples matched for sex and age were chosen to have a representative training set. The rest 240 samples (81 BN and 159 MT) were used as a testing set. Image features were extracted from 448 patients (119 BN and 153 MT in training; 57 BN and 119 MT in testing) with raw LDCT image available. In the testing set, the model trained using only protein levels had an AUC of 0.83 [0.782-0.877] (sensitivity = 71.1% [95% CI 63.6-77.6]; specificity = 82.7% [73.1-89.4]) when classifying plasma samples of lung cancers from those of benign nodules. In comparison, the imaging features-only model had an AUC of 0.874 [0.821-0.916] (sensitivity = 81.5 [73.6-87.5]; specificity = 73.7 [61.0-83.4]). The combinatorial model integrating both protein and imaging features had an AUC of 0.878 [0.830-0.921] (sensitivity = 83.2% [75.5-88.8]; specificity = 77.2% [64.8-86.2]). Notably, the combinatorial model was highly sensitive for early-stage lung cancer, achieving a sensitivity of 93.1% [78.0-98.1] when classifying stage-0 lung cancer cases(n = 29) and 94.8% [85.9-98.2] for stage-I cases (N = 58). Its sensitivity for stage II-IV (n = 7) and clinically diagnosed lung cancers cases (n = 25) were 100% [64.6-100] and 40.0% [23.4-59.3], respectively. Conclusions: This study aimed to construct a model to distinguish malignant pulmonary nodules from benign lung diseases using protein levels and LDCT imaging features. The resulted combinatorial model showed by utilizing both types of features, it was able to accurately differentiate benign and malignant pulmonary nodules, suggesting it may provide guidance for the clinical management of these nodules.

Background: Anti-U1 ribonucleoprotein (U1RNP) antibodies were associated with connective tissue diseases (CTDs), but the clinical characteristics of this antibody in Chinese myositis patients have not been studied. Objective: We aim to analyze the clinical features of myositis patients who test positive for anti-U1RNP antibodies and delineate a subgroup of myositis. Design: This is a retrospective cohort study. Methods: We reviewed the clinical data of myositis patients with anti-U1RNP antibodies and compared them to those with anti-signal recognition particle (SRP) and hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibody-associated immune-mediated necrotizing myopathy (IMNM). Results: A total of 30 adult cases were identified; median age was 47.5 years and 24 (80%) were females, and 12 patients did not coexist with myositis-specific antibodies (MSAs) (isolated anti-U1RNP). The serum creatine kinase (CK) was significantly higher in patients with isolated anti-U1RNP (2182.5 U/L versus 289 U/L, p = 0.01), and the number of patients with CK > 2000 U/L was higher compared to that in anti-U1RNP antibody patients coexisting with MSAs (66.7% versus 16.7%, p = 0.009). The prevalence of IMNM in patients’ muscle pathology with isolated anti-U1RNP was significantly higher (75%, p = 0.003). Skin rashes were less common in isolated anti-U1RNP group ( p < 0.05). Of the 25 individuals with available pulmonary high-resolution CT (HRCT), 14 (56%) were diagnosed with interstitial lung disease (ILD). The incidence of muscular weakness, dysphagia, or levels of CK was not different between the isolated anti-U1RNP antibody individuals and the anti-HMGCR or SRP-IMNM groups ( p > 0.05). But the frequency of Raynaud’s phenomenon, arthritis, and membrane attack complex (MAC) deposits in myositis patients with isolated anti-U1RNP antibodies were higher than in anti-HMGCR and SRP-IMNM (all p < 0.005). There was no difference between anti-U1RNP patients with and without Ro-52 ( p > 0.05). Isolated anti-U1RNP individuals showed marked improvements in muscle strength, and the remission rate in 1 and 2 years was significantly higher than that in anti-HMGCR and SRP-IMNM ( p < 0.05). Conclusions: The clinical and pathological features of myositis patients with isolated anti-U1RNP antibodies were similar to IMNM. Arthritis and ILD are the most common extramuscular clinical features. Most respond well to treatment and have a good prognosis.

Objective To investigate the role of bronchoalveolar lavage (BAL) in DM-associated interstitial lung disease (ILD). Methods We retrospectively reviewed the medical records of patients with DM-ILD who underwent bronchoscopy between October 2015 and September 2019. We then collated clinical features, laboratory data and bronchoscopy findings. The follow-up study was terminated on the 1 May 2020. Results A total of 113 DM-ILD patients were included in this study, including 27 patients with acute/subacute interstitial pneumonia (A/SIP) and 86 patients with chronic interstitial pneumonia (CIP). The A/SIP group had significantly lower proportions of lymphocytes and eosinophils in the bronchoalveolar lavage fluid (BALF) than the CIP group, but had a significantly higher proportion of neutrophils. Pathogens were discovered in BALF from 28 (24.8%) patients. Twenty-five (22.1%) patients commenced or changed antibiotic therapy on the basis of their bronchoscopy results. Lymphopenia and intensive care unit care were significantly associated with pathogen-positive BALF findings. Complications of bronchoscopy occurred in nine (8.0%) patients; fever (5.3%) was the most common complication. Twenty-five deaths (25/106, 23.6%) were observed during a mean follow-up of 22 months. Age, A/SIP and anti-MDA5 antibody were identified as independent predictors of a poor outcome, while mechanic's hands was an independent protective factor. However, cellular and pathogen findings in BALF had no significant influence on 30-day or overall mortality. Conclusion Bronchoscopy is a relatively useful instrument to evaluate ILD in patients with DM, and BAL can improve the diagnosis of infection. However, cellular and pathogen findings from BALF had no significant influence on prognosis.

目的:在中国特发性炎性肌病(IIM)患者中验证2018年欧洲神经肌肉中心制定的皮肌炎(2018ENMC-DM)标准.方法:回顾性收集2008年5月～2020年10月于中日友好医院风湿免疫科住院的IIM患者的临床资料、实验室检查及病理资料.分别按照1975年Bohan&Peter(B&P)、2017年美国风湿病学会/欧洲抗风湿病联盟(EULAR/ACR)及2018 ENMC-DM标准对DM患者进行重新诊断分类,比较各诊断标准对DM的敏感性、特异性.结果:共纳入成人IIM 1370例.其中符合2018 ENMC-DM标准、EULAR/ACR标准和1975 B&P标准诊断的DM患者分别为671例、693例和913例.3个标准诊断DM的敏感性为73％、72％和88％,特异性为91％、86％和69％.2018 ENMC-DM标准在有肌活检时诊断DM的敏感性和特异性为73％和88％,同时有肌活检和肌炎特异性抗体(MSA)时的敏感性和特异性为76％和97％.结论:本研究首次在中国DM人群中验证了2018 ENMC-DM新诊断分类标准,显示其在同时包含肌活检和MSA时诊断DM的特异性优于之前标准.

Objective In the current study, we aimed to assess resistin mRNA levels in the peripheral blood mononuclear cells (PBMCs) of dermatomyositis patients with interstitial lung disease (DM-ILD) and their correlation with disease activity. Methods We detected resistin mRNA levels in the PBMCs of 37 DM-ILD, 8 DM patients without ILD, and 19 healthy control (HC) subjects by performing quantitative reverse transcription real-time polymerase chain reaction analysis. Associations between resistin expression levels and major clinical manifestations, laboratory examinations, and disease activity were also analyzed. In addition, resistin expression in lung specimens from patients with DM-ILD was examined via immunohistochemistry and immunofluorescence. Results Resistin mRNA levels in PBMCs were significantly higher in DM-ILD than that in DM patients without ILD and HCs ( p = 0.043, 0.014, respectively). Among these DM-ILD patients, the resistin levels were significantly elevated in those with rapidly progressive ILD than in those with chronic ILD ( p = 0.012). The resistin mRNA levels in DM-ILD positively correlated with serum alanine aminotransferase (r = 0.476, p = 0.003), aspartate aminotransferase (r = 0.488, p = 0.002), lactate dehydrogenase (r = 0.397, p = 0.014), C-reactive protein (r = 0.423, p = 0.008), ferritin (r = 0.468, p = 0.003), carcinoembryonic antigen (r = 0.416, p = 0.011), carbohydrate antigen 125 (r = 0.332, p = 0.047), interleukin-18 (r = 0.600, p < 0.001), and lung visual analog scale values (r = 0.326, p = 0.048), but negatively correlated with the diffusing capacity of carbon monoxide (DLco)% (r = −0.447, p = 0.041). Immunohistochemical analysis of resistin showed its elevated expression in the macrophages, alveolar epithelial cells, and weak fibrotic lesions from patients with DM-ILD. Immunofluorescence staining confirmed CD68+ macrophages co-express resistin. Conclusions Resistin levels were increased in patients with DM-ILD and associated with disease activity and ILD severity. Therefore, resistin may participate in the pathogenesis of DM-ILD and may act as a useful biomarker.

OBJECTIVE:This study was undertaken to investigate the long-term survival rates and prognostic factors in patients with idiopathic inflammatory myopathies (IIMs) based on myositis-specific antibody (MSA) stratification.METHODS:Exactly 628 patients with an IIM were included. Kaplan-Meier survival curves, univariate, and multivariate Cox regression were used to analyze the outcomes and risk factors.RESULTS:The cumulative 1-, 5-, and 10-year survival rates for IIM patients overall were 91.4%, 82.8%, and 75.6%, respectively. The survival rate in the MSA subset was significantly different (P < 0.001). The 1- and 10-year survival rates in the anti-melanoma differentiation-associated protein 5 (anti-MDA-5)-positive subgroup were 79.5% and 58.5%, respectively, which were the lowest among all subgroups. The 10-year survival rate of anti-signal recognition particle (anti-SRP)-positive patients was the highest (96.4%). Independent risk factors that impacted the long-term prognosis for IIM patients included rapidly progressive interstitial lung disease (RP-ILD), malignancy, and elevated serum ferritin levels (hazard ratio [HR] 17.47, 20.36, and 9.15, respectively, P < 0.01), whereas disease duration was a protective factor (HR 0.27, P = 0.003). Among these subsets, the strongest independent risk factor for death in the anti-MDA-5-positive subgroup was RP-ILD (HR 3.4, P = 0.017). Malignancy was an independent risk factor in the anti-aminoacyl-tRNA synthetase antibody-positive, anti-transcription intermediary factor 1γ-positive, and MSA-negative subgroups (HR 46.69, 6.65, and 4.48, respectively; P < 0.001). RP-ILD was also a risk factor in the prognosis of individuals in the MSA-negative subgroup (HR 72.28, P < 0.001).CONCLUSION:Despite favorable overall survival in patients with IIM, the anti-MDA-5-positive subgroup had the highest mortality rate among all MSA subgroups, highlighting the distinctive prognosis for patients with different MSAs. RP-ILD and malignancy are the most common causes of death in IIM patients.

Abstract Objective Immune-mediated necrotising myopathy (IMNM) is a subset of idiopathic inflammatory myopathies (IIM) characterized by significantly elevated creatine kinase level, muscle weakness and predominant muscle fibre necrosis in muscle biopsy. This study aimed to investigate the clinical and pathological characteristics of patients with IMNM in a single-centre muscle biopsy cohort. Methods A total of 860 patients who had muscle biopsy reports in our centre from May 2008 to December 2017 were enrolled in this study. IMNM was diagnosed according to the 2018 European Neuromuscular Centre (ENMC) clinicopathological diagnostic criteria for IMNM. Results The muscle biopsy cohort consisted of 531 patients with IIM (61.7%), 253 patients with non-IIM (29.4%), and 76 undiagnosed patients (8.8%). IIM cases were classified as IMNM (68[7.9%]), dermatomyositis (346[40.2%]), anti-synthetase syndrome (82[9.5%]), polymyositis (32[3.7%]), and sporadic inclusion body myositis (3[0.3%]). Limb girdle muscular dystrophy (LGMD) 2B and lipid storage myopathy (LSM) are the two most common non-IIM disorders in our muscle biopsy cohort. IMNM patients had a higher onset age (41.57 ± 14.45 vs 21.66 ± 7.86 and 24.56 ± 10.78, p < .0001), shorter duration (21.79 ± 26.01 vs 66.69 ± 67.67 and 24.56 ± 10.78, p < .0001), and more frequent dysphagia (35.3% vs. 3.4 and 6.3%, p = .001) than LGMD 2B and LSM patients. Muscle biopsy from IMNM showed more frequent muscle fibre necrosis (95.6% vs 72.4 and 56.3%, p < .0001), overexpression of major histocompatibility complex-I on sarcolemma (83.8% vs 37.9 and 12.9%, p < .0001), and CD4+ T cell endomysia infiltration (89.7% vs 53.6 and 50%, p < .0001) compared with those from LGMD 2B and LSM patients. Conclusions It is easy to distinguish IMNM from other IIM subtypes according to clinical symptoms and myositis specific antibodies profiles. However, distinguishing IMNM from disorders clinically similar to non-IIM needs combined clinical, serological and pathological features.

OBJECTIVE:Myofiber necrosis is a significant pathologic characteristic of idiopathic inflammatory myopathies (IIMs), and its molecular mechanism is largely unknown. Necroptosis is a recently identified form of regulated necrotic cell death, and its activation might have crucial biologic consequences. The aim of the present study was to investigate the role of necroptosis in IIM muscle damage.METHODS:Western blot and immunohistochemistry analyses were performed to examine the expression of receptor-interacting protein 3 (RIP-3) and mixed-lineage kinase domain-like (MLKL) proteins in 26 IIM patients and 4 healthy controls, as well as necroptosis-related damage-associated molecular pattern molecules. Tumor necrosis factor (TNF) was used to stimulate cultured C2C12 myoblasts, and the involvement of necroptosis in cell death of C2C12 cells was studied in vitro.RESULTS:The expression of RIP-3 and MLKL proteins and their phosphorylated forms was significantly increased in the muscle tissue of IIM patients compared to that of healthy controls. The expression levels of RIP-3 and MLKL proteins were associated with the severity of muscle damage in patients with IIM. Significant colocalization of MLKL with high mobility group box chromosomal protein 1 in necrotizing myofibers was observed in muscle biopsy tissue from patients with IIM. Stimulation of C2C12 myoblasts with TNF and a pan-caspase inhibitor, Z-VAD, resulted in the overactivation of necroptosis and significantly increased necrotic cell death. Strategies involving either inhibition of necroptosis with necrostatin-1 or knockdown of MLKL expression successfully prevented necroptosis-induced cell death of C2C12 cells.CONCLUSION:These findings demonstrate that overactivated necroptosis contributes to muscle damage in IIMs and suggest that necroptosis inhibitors could represent a new therapeutic target in the treatment of IIMs.

Objective: To investigate the association of the serum levels of anti-transcriptional intermediary factor 1 (TIF1)-gamma autoantibodies with the clinical and pathological characteristics, as well as the prognosis of adult patients with dermatomyositis (DM). Methods: Eighty-seven adult DM patients with anti-TIF1-gamma autoantibodies positive screened by immunoblotting assay were enrolled in the study. The presence and levels of anti-TIF1-gamma autoantibodies were examined through enzyme-linked immunosorbent assay (ELISA). Muscle biopsy specimens were obtained from 52 patients, and immunohistochemistry was performed to visualize major histocompatibility complex (MHC)-I, CD3, CD20 and C5b-9. Muscle biopsy scores and disease activity were evaluated. Results: A total of 80 patients were positive for anti-TIF1-gamma autoantibodies confirmed by ELISA assay, including 30 cancer-associated myositis (CAM) and 50 non-CAM. Serum levels of anti-TIF1-gamma autoantibodies did not significantly differ between the CAM and non-CAM groups. The levels of anti-TIF1-gamma were associated with disease activity scores. A total of 63.9% of non-CAM patients displayed a classical DM pathological phenotype. Conversely, CAM patients presented with classical DM (25%), immune-mediated necrotizing myopathy (25%), non-specific myositis (32.3%), and normal (18%) phenotypes of muscle biopsy. Anti-TIF1-gamma autoantibody levels were positively associated with muscle biopsy total scores, muscle fiber scores and inflammatory infiltration scores in the non-CAM patients but not in the CAM patients. The survival rate of CAM patients presenting with high anti-TIF1-gamma autoantibody levels was lower than that of patients with low levels. However, no difference in survival rate was observed in the non-CAM group between high and low autoantibody levels. Conclusion: The distinct associations of anti-TIF1-gamma autoantibody levels with disease activity, muscle histopathology damage and outcome indicated that different pathogenesis might be involved in DM with or without cancer.

OBJECTIVE:Anti-mitochondrial antibodies (AMAs) can be detected in some idiopathic inflammatory myopathy (IIM) patients. We aimed to investigate the clinical features of IIM patients with AMAs.METHODS:We retrospectively analysed 1,167 consecutive patients with IIM for AMA-associated myositis and compared them to age- and gender-matched AMA-negative IIM patients.RESULTS:Twenty-nine patients (2.5%) were identified with AMA-positive myositis; eight of them had primary biliary cholangitis (PBC). There were no significant differences in skin rash, dysphagia, interstitial lung disease, and muscle strength between AMA-positive patients and AMA-negative patients. Of 23 cases, 12 (52.2%) showed immune-mediated necrotizing myopathy (IMNM)-like pathological features. amongst AMA-positive patients, 11 of 16 patients with isolated anti-AMAs were classified as IMNM which was significantly higher than that of patients with coexistent anti-AMAs and myositis-specific antibodies (p = 0.026). Moreover, subclinical cardiac involvement was significantly more common in AMA-positive patients than in AMA-negative patients (21/29 VS 33/116, p<0.001). In addition, patients without PBC had a significantly higher incidence of abnormal echocardiography findings than that of patients with PBC (p = 0.009). Patients without heart abnormalities took significantly less time to achieve disease remission and prednisone tapering to <10 mg than patients with heart abnormalities (p = 0.000 and p = 0.001, respectively).CONCLUSIONS:IMNM was a major histopathological finding in IIM patients with isolated AMAs. AMAs were significantly associated with subclinical cardiac involvement in IIM. PBC seemed to be a protective factor for abnormal echocardiography findings in AMA-positive patients. Patients without heart involvement took less time to achieve disease remission and prednisone tapering off.

OBJECTIVE:To investigate the clinical and pathological features of immune-mediated necrotic myopathies (IMNM) with different myositis-specific antibodies (MSAs).METHODS:In the study, 104 IMNM patients who met any of the following three criteria were selected from idiopathic inflammatory myopathy patients who had MSAs results and underwent muscle biopsy from 2008 to 2018 in China-Japan Friendship Hospital: (1) Anti-signal recognition particle (SRP) antibody positive; (2) Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibody positive; (3) MSAs negative and consistent with the pathological diagnostic criteria of IMNM defined by the European Neuromuscular Centre in 2004. The clinical, laboratory and muscle pathological information of the IMNM patients were retrospectively collected and compared in anti-SRP, anti-HMGCR and MSAs negative groups.RESULTS:Of 104 IMNM patients, 47 patients (45.2%) were positive for anti-SRP antibody, 23 (22.1%) were positive for anti-HMGCR antibody, and 34 (32.7%) were negative for MSAs. The common symptoms of IMNM patients were muscle weakness (92.3%), elevated serum creatine kinase level (92.3%), dysphagia (33.7%) and interstitial lung diseases (ILD) (49.5%). The anti-HMGCR-positive patients were more frequent to have "V" sign (30.4% vs. 4.3% and 5.9%, P<0.01) as compared with the anti-SRP-positive and MSAs-negative patients. The incidence of ILD in the anti-SRP-positive patients was higher than that in the anti-HMGCR-positive and MSAs negative patients (64.4% vs. 34.8% and 29.0%, P<0.01). The prevalence of the patients combined with other connective tissue diseases in MSAs-negative IMNM was higher than that in the other two groups (32.4% vs. 8.5% and 4.3%, P<0.01). 93.3% of the anti-SRP-positive patients were found with antinuclear antibody positivity, higher than those of the anti-HMGCR-positive and MSAs-negative patients (93.3% vs. 36.4% and 58.8%, P<0.001). The common pathological features of IMNM were muscle fibre necrosis (94.2%), regeneration (67.3%) and phagocytosis (65.4%), overexpression of major histocompatibility complex1 on sarcolemma (78.8%), infiltration of CD4+ T cells (81.7%) and CD68+ macrophage (79.8%) and expression of membrane attack complex (MAC) (77.8%). The endomysial infiltration of CD4+ T cells and CD68+ macrophage and MAC expression on sarcolemma in the MSAs-negative group were more common than that in the anti-SRP and anti-HMGCR groups (88.2% vs. 57.4% and 60.9%, 91.2% vs. 59.1% and 38.1%, 76.5% vs. 45.5% and 42.9%, respectively, P<0.01).CONCLUSION:There is heterogeneity in anti-SRP-positive, anti-HMGCR-positive or MSAs-negative patients. The detection of MSAs and performing of muscle biopsy are useful for distinguishing different types of IMNM.