Novel endotypes of antisynthetase syndrome identified independent of anti-aminoacyl transfer RNA synthetase antibody specificity that improve prognostic stratification.

OBJECTIVES: To systemically analyse the heterogeneity in the clinical manifestations and prognoses of patients with antisynthetase syndrome (ASS) and evaluate the transcriptional signatures related to different clinical phenotypes. METHODS: A total of 701 patients with ASS were retrospectively enrolled. The clinical presentation and prognosis were assessed in association with four anti-aminoacyl transfer RNA synthetase (ARS) antibodies: anti-Jo1, anti-PL7, anti-PL12 and anti-EJ. Unsupervised machine learning was performed for patient clustering independent of anti-ARS antibodies. Transcriptome sequencing was conducted in clustered ASS patients and healthy controls. RESULTS: Patients with four different anti-ARS antibody subtypes demonstrated no significant differences in the incidence of rapidly progressive interstitial lung disease (RP-ILD) or prognoses. Unsupervised machine learning, independent of anti-ARS specificity, identified three endotypes with distinct clinical features and outcomes. Endotype 1 (RP-ILD cluster, 23.7%) was characterised by a high incidence of RP-ILD and a high mortality rate. Endotype 2 (dermatomyositis (DM)-like cluster, 14.5%) corresponded to patients with DM-like skin and muscle symptoms with an intermediate prognosis. Endotype 3 (arthritis cluster, 61.8%) was characterised by arthritis and mechanic's hands, with a good prognosis. Transcriptome sequencing revealed that the different endotypes had distinct gene signatures and biological processes. CONCLUSIONS: Anti-ARS antibodies were not significant in stratifying ASS patients into subgroups with greater homogeneity in RP-ILD and prognoses. Novel ASS endotypes were identified independent of anti-ARS specificity and differed in clinical outcomes and transcriptional signatures, providing new insights into the pathogenesis of ASS.

Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial.

OBJECTIVES: This phase 2b, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of telitacicept, a novel fusion protein that neutralises signals of B lymphocyte stimulator and a proliferation-inducing ligand, in active systemic lupus erythematosus (SLE). METHODS: Adult patients with active SLE (n=249) were recruited from 29 hospitals in China and randomised 1:1:1:1 to receive subcutaneous telitacicept at 80 mg (n=62), 160 mg (n=63), 240 mg (n=62) or placebo (n=62) once weekly in addition to standard therapy. The primary endpoint was the proportion of patients achieving an SLE Responder Index 4 (SRI-4) response at week 48. Missing data were imputed using the last observation carried forward method. RESULTS: At week 48, the proportion of patients achieving an SRI-4 response was 75.8% in the 240 mg telitacicept group, 68.3% in the 160 mg group, 71.0% in the 80 mg group and 33.9% in the placebo group (all p<0.001). Significant treatment responses were observed in secondary endpoints, including a ≥4-point reduction on the Systemic Lupus Erythematosus Disease Activity Index, a lack of Physician's Global Assessment score worsening and a glucocorticoid dose reduction in the 240 mg group. Telitacicept was well tolerated, and the incidence of adverse events and serious adverse events was similar between the telitacicept and placebo groups. CONCLUSIONS: This phase 2b clinical trial met the primary endpoint. All telitacicept groups showed a significantly higher proportion of patients achieving an SRI-4 response than the placebo group at week 48, and all doses were well tolerated. These results support further investigations of telitacicept in clinical trials involving more diverse populations and larger sample sizes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02885610).

Longitudinal study of patients with anti-SAE antibody positive dermatomyositis: a multicenter cohort study in China.

OBJECTIVES: To describe the longitudinal study and long-term prognosis of multicentre large inception cohort of patients with anti-SAE positive DM. METHODS: We retrospectively recruited patients with anti-SAE+DM in four tertiary referral centers from China between March 2005 and December 2022. Long-term survival analysis was performed in the enrolled patients. The Myositis Damage Index (MDI) and Cutaneous Disease Area and Severity Index (CDASI) were used to evaluate the degree of different organ damage and the extent of skin rashes. Longitudinal computed tomographic (CT) patterns were analyzed. Phenotypes were characterized using unsupervised cluster analysis. RESULTS: All-cause death occurred in 10.5% (4/38) of all patients, in which three patients succumbed to malignancies at 13, 18, and 36 months. Most patients had favorable long-term outcomes, 35.3% of them were in drug-free remission. Skin rashes showed significant improvement evaluated by CDASI with time. However, damage to different systems was observed in 70.6% of the surviving patients using the MDI, which mainly consisted in skin damage, accounting for 47.1%. Nine patients with anti-SAE+DM associated interstitial lung disease (ILD) underwent repeat CT showed marked radiological improvement at 6 months or being stable after 12 months. In further, different characteristics and outcomes were also showed in three clusters identified by unsupervised analysis. CONCLUSIONS: Anti-SAE+DM is characterized with lower mortality rate and the development of malignancies being the primary cause of death. Patients who survived showed notable cutaneous damage, while the ILD tends to stabilize. Clusters identified with unsupervised analysis could assist physicians in identifying higher risk of mortality.

Clinical and prognostic associations of anti-Jo-1 antibody levels in patients with antisynthetase syndrome.

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 (ß = 0.002, p = 0.001), muscle (ß = 0.003, p < 0.0001), and pulmonary (ß = 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.

Polymyositis is a rare and favourable outcome subtype of idiopathic inflammatory myopathy in Chinese patients.

OBJECTIVES: To investigate the prevalence and characteristics of typical polymyositis (PM) in Chinese patients with idiopathic inflammatory myopathy (IIM). METHODS: Patients diagnosed with IIM according to the 2017 EULAR/ACR criteria were included. Serological aspects including myositis-specific antibodies (MSA) and pathological data were re-evaluated. The diagnosis of typical PM was strictly done using the pathological criteria, while excluding other IIM subtypes such as dermatomyositis (DM), immune-mediated necrotising myopathies (IMNM), anti-synthetase syndrome (ASS), and sporadic inclusion body myositis (sIBM), based on their respective diagnostic criteria. RESULTS: A total of 544 IIM patients with muscle biopsy were involved, and 129 of them were diagnosed with initial PM according to the 2017 EULAR/ACR criteria. Only 6 (1.1%, 6/544) patients met the strict definition of typical PM after re-evaluation. Patients with typical PM were MSA-negative (100% vs. 35.7%, p=0.003) and had CD8+ T cells surrounding or invading non-necrotic muscle fibres in muscle biopsies (100% vs. 7.8%, p<0.001) compared to the initially diagnosed PM patients. All typical PM patients achieved clinical remission at the second-year follow-up. Typical PM patients had a favourable prognosis compared to MSA-negative IMNM and unspecific myositis patients. CONCLUSIONS: Strictly defined typical PM is a rare clinical subtype in Chinese IIM patients. Typical PM patients with classical pathology were MSA-negative and responded well to treatment and had a favourable prognosis. It is crucial for clinicians to combine clinical, serological, and pathological features to properly distinguish PM from other IIM subtypes.

Nintedanib could potentially lead to improvements in anti-melanoma differentiation-associated 5 dermatomyositis-associated interstitial lung disease.

OBJECTIVES: To determine the efficacy and safety of nintedanib in patients with anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis-associated interstitial lung disease (anti-MDA5+ DM-ILD). METHODS: The study was a retrospective cohort design that evaluated patients with anti-MDA5+ DM who either received or did not receive nintedanib. Clinical symptoms, laboratory tests, and survival were compared in the two groups using a propensity score-matched analysis. The primary endpoint was mortality, while adverse events were recorded descriptively. RESULTS: After propensity score matching, 14 patients who received nintedanib (nintedanib+ group) and matched 56 patients who did not receive nintedanib (nintedanib- group) were enrolled. Compared with the nintedanib- group, the nintedanib+ group had a lower incidence of heliotrope and arthritis, higher lymphocyte counts, lower serum ferritin levels, and greater 12-month survival (all p<0.005). Although lung function, HRCT score, and lung VAS were not statistically different between the two groups, the longitudinal study showed significant improvement in HRCT scores (p=0.028) and pulmonary VAS (p=0.019) in the nintedanib+ group. Adverse events occurred in 28.6% of patients, with the most common adverse event with nintedanib being diarrhoea. CONCLUSIONS: Nintedanib may be effective for improving clinical symptoms, laboratory parameters, lung lesions, and survival in anti-MDA5+ DM. Diarrhoea was the most common adverse event associated with nintedanib, although the drug was well tolerated by most patients.

Expansion of exhausted CD8+ T cells associates with increased pulmonary fungal infection risk in anti-melanoma differentiation associated gene 5 dermatomyositis.

OBJECTIVES: Anti-MDA5+ dermatomyositis was associated with poor prognosis due to the high incidence of rapid progressive interstitial lung disease, pulmonary infection. The aim of this study is to investigate the abundance and clinical relevance of exhaustion markers on peripheral CD8 T cells from patients with idiopathic inflammatory myopathy (IIM). METHODS: Twenty-nine healthy controls (HCs) and 71 patients with IIM were enrolled, including 42 with anti-MDA5+ and 18 with anti-MDA5- dermatomyositis (DM) and 11 with anti-synthetase syndrome (ASS). Flow cytometry was applied to detect PD-1, TIM-3 and LAG-3 in CD8 T cells. The clinical associations of the CD8 T cell exhaustion phenotype in patients with anti-MDA5+ DM were analysed. RESULTS: CD8 T cells from patients with anti-MDA5+ DM showed significantly increased LAG-3, TIM-3 and PD-1 compared to those from patients with anti-MDA5- IIM (18 with anti-MDA5- DM and 11 with ASS) or HCs (adjusted p all < 0.05). CD8 T cells with distinct exhaustion levels were all significantly increased in anti-MDA5+ DM patients compared with HCs (p all < 0.05). Patients with high level of PD-1+ TIM-3+LAG-3+ CD8+ T cells had a significant higher incidence of pulmonary fungal infections but lower counts of CD4+ and CD8+ T cells. ROC analysis revealed that the frequency of PD-1+TIM-3+LAG-3+CD8+ T cell significantly predicted pulmonary fungal infections (area under the curve: 0.828). CONCLUSIONS: CD8 T cells from patients with anti-MDA5+ DM show significant exhausted phenotype, and increased exhausted CD8 T cells were associated with high risk of pulmonary fungal infection.

Performance of the 2017 EULAR/ACR Classification Criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: a scoping review.

The 2017 EULAR/ACR classification criteria for adult/juvenile idiopathic inflammatory myopathies (IIM) were established using a data-driven approach by an international group of myositis experts to allow classification of IIM and its major subtypes. Since their publication, the performance of the criteria has been tested in multiple cohorts worldwide and significant limitations have been identified. Moreover, the understanding and classification of IIM have evolved since 2017. This scoping review was undertaken as part of a large international project to revise the EULAR/ACR criteria and aims to i) summarise the evidence from the current literature on the performance characteristics of the 2017 EULAR/ACR classification criteria in various cohorts and IIM subtypes, and ii) delineate the factors that need to be considered in the revision of the classification criteria. A systematic search of Medline (via PubMed), Cumulative Index to Nursing and Allied Health Literature, and conference abstract archives was conducted independently by three investigators for studies on the EULAR/ACR criteria published between October 2017 and January 2023. This scoping review of 19 articles and 13 abstracts revealed overall good performance characteristics of the EULAR/ACR criteria for IIM, yet deficiencies in lack of inclusion of certain IIM subtypes, such as immune mediated necrotising myopathy, amyopathic dermatomyositis, antisynthetase syndrome and overlap myositis. Published modifications that may improve the performance characteristics of the criteria for classification of IIM subtypes were also summarised. The results of this review suggest that a revision of the EULAR/ACR criteria is warranted.

Collating the voice of people with autoimmune diseases: Methodology for the Third Phase of the COVAD Studies.

INTRODUCTION: The growing recognition of holistic patient care highlights the various factors shaping the quality of life of individuals with autoimmune and rheumatic diseases (AIRDs). Beyond the traditional disease measures, there is an emerging acknowledgment of the less-explored aspects, including subjective well-being, social determinants of health, comorbidities, mental health, and medication adherence. Moreover, digital health services have empowered patients to engage actively in decision-making alongside clinicians. To explore these domains within the context of AIRDs, the "Collating the Voice of People with Autoimmune Diseases" COVAD survey was conceived, a successor of the previous two COVAD surveys. In this document, we present the study protocol in comprehensive detail. METHODS: The COVAD-3 survey is a cross-sectional patient self-reported e-survey incorporating multiple widely accepted scales/scores to assess various aspects of patients' lifestyles objectively. To ensure the survey's accuracy and usability across diverse regions, it will be translated into multiple languages and subjected to rigorous vetting and pilot testing. It will be distributed by collaborators via online platforms and data will be collected from patients with AIRDs, and healthy individuals over eight months. Data analysis will focus on outcome measures related to various social, demographic, economic, and psychological factors. CONCLUSION: With the increasing awareness to adopt a holistic treatment approach encompassing all avenues of life, the COVAD-3 survey aims to gain valuable insights into the impact of social, demographic, economic, and psychological determinants of health on the subjective well-being in patients with AIRDs, which will contribute to a better understanding of their overall health and well-being.

Peripheral lymphocyte count defines the clinical phenotypes and prognosis in patients with anti-MDA5-positive dermatomyositis.

OBJECTIVE: To explore the role of peripheral lymphocyte count in phenotyping and prognosis prediction in dermatomyositis (DM) patients with anti-MDA5 antibodies. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: Lymphopenia is a unique manifestation of anti-MDA5+ DM. Peripheral lymphocyte count can define clinical phenotypes and predict prognosis in anti-MDA5+ DM.

High prevalence and mortality of Pneumocystis jirovecii pneumonia in anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: To identify potential risk factors and prognostic factors of Pneumocystis jirovecii pneumonia (PJP) infection in anti-melanoma differentiation-associated gene 5 antibody-positive DM (anti-MDA5+ DM) patients, and to evaluate the diagnostic performance of metagenomic next-generation sequencing (mNGS). METHODS: Anti-MDA5+ DM patients who underwent mNGS or real-time PCR for PJP detection were recruited. The potential risk factors for PJP occurrence and death were analysed via Logistic regression and Cox proportional hazards regression, respectively. The diagnostic efficacy of mNGS was compared with the conventional methods. RESULTS: 91 patients were enrolled and 44 were assigned to PJP+ group. The PJP detection rate was 48.4%. PJP often occurred in the first 3 months (68.2%) of the disease; this period also showed the highest mortality rate (20.5%). Fever and increased lactate dehydrogenase (LDH) were independent risk factors for PJP occurrence, while trimethoprim-sulfamethoxazole (TMP/SMZ) prophylaxis was an independent protective factor (all P < 0.05). Older age and increased LDH were predictors for mortality in patients with anti-MDA5+ DM and PJP (all P < 0.05). In addition, we found that mNGS had a sensitivity of 100.0% and specificity of 90.0% in diagnosing PJP, with the highest area under the curve of 0.95 (P < 0.001). CONCLUSION: PJP has high prevalence and mortality in anti-MDA5+ DM. It is crucial for clinicians to identify high-risk patients and promptly institute TMP/SMZ to prevent PJP. mNGS is the preferred approach for pathogen detection in anti-MDA5+ DM when PJP is suspected.

Comparison of clinical features between patients with anti-synthetase syndrome and dermatomyositis: Results from the MYONET registry.

OBJECTIVES: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations, and malignancy, between adults with anti-synthetase syndrome (ASyS) and dermatomyositis (DM). METHODS: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1É£/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V sign, erythroderma, and/or periorbital rash). RESULTS: In total 1,054 patients were included (DM, n = 405; ASyS, n = 649). In ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease, and cardiac involvement differentiated ASyS-DMskin from DM (all p< 0.001), whereas higher frequency of any of four DM-type rashes: heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%) differentiated DM from ASyS-DMskin (all p< 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both p< 0.001). CONCLUSION: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.

Efficacy and Safety of Tofacitinib in Anti-Melanoma Differentiation-Associated 5 Gene Antibody-Positive Dermatomyositis.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of tofacitinib for the treatment of anti-melanoma differentiation-associated 5 gene (anti-MDA5) antibody-positive dermatomyositis (DM). METHODS: This study included 52 patients with anti-MDA5 antibody-positive DM (MDA5 + DM) who were treated with tofacitinib and followed up. Clinical and laboratory data of these patients were recorded between January 2019 and June 2022. SPSS was used for all statistical analyses. RESULTS: The mean age of patients with MDA5 + DM was 45 ± 12.4 years, and the median disease duration was 6.5 months (range, 3-13 months). The mean dosage of glucocorticoids was 34.7 ± 20.9 mg/d at the initiation of tofacitinib therapy. Overall, 47 patients were followed up for a mean duration of 7.8 ± 6.2 months. We found that the clinical symptoms of 28 patients (59.6%) were improved, but 1 patient (2.1%) died because of severe infection. Moreover, complications occurred in 25 patients (53.2%), among whom 19 patients had infections. Older age and C-reactive protein levels close to the upper value in reference range at the initial treatment were found to be the potential risk factors of infection. Furthermore, patients with cutaneous ulcers were found to have a lower risk of infection. CONCLUSION: Tofacitinib can be used as a potential therapeutic option for MDA5 + DM. The occurrence of infection requires special attention during treatment, particularly in patients with older age and C-reactive protein levels close to the upper value in reference range.

Biomarkers of disease activity in dermatomyositis.

PURPOSE OF REVIEW: This review provides updates regarding biomarker studies that address key clinical unmet needs, which relate to the evaluation of the disease activity in patients with dermatomyositis. RECENT FINDINGS: Increasing evidence supports that the serum levels of dermatomyositis-specific antibodies (DM-MSAs), which include anti-Mi-2, anti-NXP2, anti-MDA5, anti-TNF1-γ, and anti-SAE, are correlated with the disease activity. Moreover, serial measurements of DM-MSA levels may help to predict the disease status. Beyond the MSA, macrophage activation-related biomarker-soluble CD163, CD206, neopterin, and galectin-3/9 are the most currently talked biomarkers for disease activity in dermatomyositis; new circulating T-cell subsets CD4+CXCR5+CCR7loPD-1hi and TIGIT+CD226+ CD4 T cells can potentially harbor biomarkers of disease activity in dermatomyositis. In addition, LDGs and NETs were also shown to be correlated with the disease activities of dermatomyositis. SUMMARY: Promising candidate biomarkers are now available for evaluating disease activity in dermatomyositis. These biomarkers need external validation in other large cohort studies.

Plasma exosomal RNAs have potential as both clinical biomarkers and therapeutic targets of dermatomyositis.

OBJECTIVES: DM is characterized by skeletal muscle weakness and cutaneous manifestations. Plasma exosomes (EXOs) contain proteins, RNAs, DNA, and lipid cargoes and are transferred among cells. If thoroughly investigated, plasma EXO RNAs could potentially improve our understanding of DM pathogenesis. We aimed to identify potential new biomarkers and therapeutic targets for DM. METHODS: The RNA (mRNA, miRNA and lncRNA) profiles of plasma EXOs were evaluated by sequencing on the Illumina HiSeq 3000 platform. Differentially expressed (DE) RNAs and bioinformatic analyses were performed. Human skeletal muscle myoblasts cells (HSkMCs) were stimulated with plasma EXOs, rapamycin or IFN-ß. Real-time PCR and western blot analysis were used to detect related genes and proteins. RESULTS: A total of 689 DE mRNAs, 53 DE miRNAs and 452 DE lncRNAs were identified in DM plasma EXOs. Bioinformatic analysis inferred that plasma EXOs were secreted mainly by CD8+ T cells, regulatory T cells and natural killer cells. The DE miRNAs participated in the autophagy, TGF-ß and Wnt signalling pathways. Three DE miRNAs (hsa-miR-125a-3p, hsa-miR-1246 and hsa-miR-3614-5p) were correlated with serological indices, organ involvement and myositis-specific autoantibodies. The DE lncRNAs participated in autophagy, IFN-ß production and mTOR signalling. DM plasma EXOs can induce autophagy in HSkMCs by regulating three miRNAs (hsa-miR-125a-3p, hsa-miR-1246 and hsa-miR-3614-5p) and three lncRNAs (ENST00000584157.1, ENST00000523380.1 and ENST00000560054.1), which formed an autophagy network, playing a role in muscle damage. CONCLUSION: Our study provides an overview of distinct RNA profiles in DM plasma EXOs, and verified some miRNAs as potential biomarkers and therapeutic targets. The findings provide important clues for more in-depth explorations of plasma EXOs in DM.

Evaluation and validation of the prognostic value of anti-MDA5 IgG subclasses in dermatomyositis-associated interstitial lung disease.

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.

Clinical heterogeneities and prognoses of patients with myositis specific antibody negative dermatomyositis: a retrospective study in China.

OBJECTIVES: The clinical features of myositis specific antibody negative dermatomyositis (MSA negative DM) varied greatly, and there were few reports in the literatures. This study aimed to describe and expand the clinical phenotypes and prognoses of MSA negative DM patients. METHODS: MSA negative DM patients were identified from January 2010 to June 2020. We retrospectively reviewed the clinical features and laboratory data. The survival status was followed up until July 31. 2020 SPSS version 21.0 and R version 3.6.1 software were used for the statistical analyses. RESULTS: A total of 97 MSA negative DM patients were enrolled. The most common type of rashes was heliotrope rash (80.4%). More than half of the patients (55.7%) had interstitial lung disease (ILD), and seven of them developed rapid progressive ILD. There were eleven patients with tumours. During the follow-up, twelve patients died, of whom 5 (41.7%) died due to infection. Two phenotypes of MSA negative DM patients were identified by cluster analysis. Patients in cluster 1 developed muscle weakness, mechanic's hands, arthritis, and ILD more frequently. Patients in cluster 2 had a higher incidence of heliotrope rashes. Patients in cluster 1 tended to have worse prognoses, wherein the 1-year and 5-year survival rates (81.1% and 78.4%, respectively) were lower than those in cluster 2 (97.6% and 95.2%, respectively), with p value 0.04 and 0.056 respectively. CONCLUSIONS: Through cluster analysis, different clinical phenotypes of MSA negative DM patients were determined. The prognoses of the two subgroups were different in terms of survival rate and cause of death.

Interstitial lung disease is not rare in immune-mediated necrotizing myopathy with anti-signal recognition particle antibodies.

OBJECTIVES: The purpose was to clarify the characteristics of interstitial lung disease (ILD) in immune-mediated necrotizing myopathy (IMNM) patients with anti-signal recognition particle (SRP) antibodies. METHODS: Medical records of IMNM patients with anti-SRP antibodies were reviewed retrospectively. RESULTS: A total of 60 patients were identified. Twenty-seven (45.0%) patients were diagnosed with ILD based on lung imaging: nonspecific interstitial pneumonia (NSIP) in 17 patients (63.0%) and organizing pneumonia in 9 patients (33.3%). Reticulation pattern was identified in 17 patients (63.0%) whereas 10 cases (37.0%) showed ground glass opacity and patchy shadows by high-resolution computed tomography (HRCT). Pulmonary function tests (PFTs) were available in 18 patients, 6 (33.3%) and 10 (55.6%) patients were included in the mild and moderate group, respectively. The average age at the time of ILD onset was significantly older than those without ILD (48.6 ± 14.4 years vs. 41.2 ± 15.4 years, p < 0.05), and the frequency of dysphagia in the ILD group was higher than the group without ILD (p < 0.05). Long-term follow-up was available on 9 patients. PFTs were stable in 8 (88.9%), and the HRCT remained stable in 6 (66.7%) patients. CONCLUSIONS: ILD is not rare in IMNM patients with anti-SRP antibodies, most being characterized as mild to moderate in severity. NSIP is the principal radiologic pattern, and ILD typically remains stable following treatment.

Clinical and pathological features of immune-mediated necrotising myopathies in a single-centre muscle biopsy cohort.

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.

Clinical features, treatments and outcomes of calcinosis in adult patients with dermatomyositis: a single cohort study.

OBJECTIVE: The occurrence of calcinosis cutis as a clinical feature of dermatomyositis in adult patients is not well understood. Cohort studies of adult patients with calcinosis are rare. We systematically describe the clinical features, treatments and outcomes of adult patients with calcinosis. METHODS: We initially enrolled 627 adult DM patients. Of those enrolled, 35 (5.6%) were found to have calcinosis. We analysed the clinical features associated with calcinosis in this subgroup. The risk factors associated with calcinosis were analysed using the Poisson regression model. RESULTS: Multivariate analysis showed that a younger age at disease onset [odds ratio (OR) = 0.945, 95% CI 0.925, 0.966, P < 0.001], dysphagia (OR = 2.609, 95% CI 1.189, 5.728, P = 0.017), skin ulcer (OR = 5.705, 95% CI 3.041, 10.705, P < 0.001) and the presence of anti-nuclear matrix protein 2 antibody (OR = 5.917, 95% CI 2.754, 12.714, P < 0.001) were independently associated with calcinosis. In both the low- and high-dose prednisone treatment groups, no difference in treatment response was seen between the bisphosphonate treatment group and the group not receiving bisphosphonate treatment (P = 1.000 and P = 0.375, respectively). A follow-up study revealed that the mortality rate of the calcinosis group was 5.7%. Additionally, 60.6% of the cases had a chronic polycyclic disease course and 17.1% had mild complications secondary to calcinosis. CONCLUSION: Calcinosis is an uncommon, but significant clinical feature in adult patients with DM. Bisphosphonates were not found to effectively treat calcinosis, however, the overall health outcomes of adult DM patients with calcinosis were favourable.