Systematic review and network meta-analysis on the efficacy and safety of parmacotherapy for hand osteoarthritis.

OBJECTIVE: Hand osteoarthritis poses a significant health challenge globally due to its increasing prevalence and the substantial burden on individuals and the society. In current clinical practice, treatment options for hand osteoarthritis encompass a range of approaches, including biological agents, antimetabolic drugs, neuromuscular blockers, anti-inflammatory drugs, hormone medications, pain relievers, new synergistic drugs, and other medications. Despite the diverse array of treatments, determining the optimal regimen remains elusive. This study seeks to conduct a network meta-analysis to assess the effectiveness and safety of various drug intervention measures in the treatment of hand osteoarthritis. The findings aim to provide evidence-based support for the clinical management of hand osteoarthritis. METHODS: We performed a comprehensive search across PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials was conducted until September 15th, 2022, to identify relevant randomized controlled trials. After meticulous screening and data extraction, the Cochrane Handbook's risk of bias assessment tool was applied to evaluate study quality. Data synthesis was carried out using Stata 15.1 software. RESULTS: 21 studies with data for 3965 patients were meta-analyzed, involving 20 distinct Western medicine agents. GCSB-5, a specific herbal complex that mainly regulate pain in hand osteoarthritis, showed the greatest reduction in pain [WMD = -13.00, 95% CI (-26.69, 0.69)]. CRx-102, s specific medication characterized by its significant effect for relieving joint stiffness symptoms, remarkably mitigated stiffness [WMD = -7.50, 95% CI (-8.90, -6.10)]. Chondroitin sulfate displayed the highest incidence of adverse events [RR = 0.26, 95% CI (0.06, 1.22)]. No substantial variation in functional index for hand osteoarthritis score improvement was identified between distinct agents and placebo. CONCLUSIONS: In summary, GCSB-5 and CRx-102 exhibit efficacy in alleviating pain and stiffness in HOA, respectively. However, cautious interpretation of the results is advised. Tailored treatment decisions based on individual contexts are imperative.

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.

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.

Spontaneous pneumomediastinum in anti-MDA5-positive dermatomyositis: Prevalence, risk factors, and prognosis.

OBJECTIVE: To depict the clinical panorama of spontaneous pneumomediastinum (SPM) in anti-MDA5 antibody-positive dermatomyositis (anti-MDA5+ DM). METHODS: A total of 1352 patients with idiopathic inflammatory myopathy (IIM), including 384 anti-MDA5+ DM patients were retrospectively enrolled. The clinical profiles of anti-MDA5+ DM-associated SPM were analyzed. RESULTS: We identified that 9.4 % (36/384) of anti-MDA5+ DM patients were complicated with SPM, which was significantly higher than that of non-anti-MDA5+ DM and other IIM subtypes (P all <0.001). SPM developed at a median of 5.5 (3.0, 12.0) months after anti-MDA5+ DM onset. Anti-MDA5+ DM patients complicated with SPM showed a significantly higher frequency of fever, dyspnea, and pulmonary infection including viral and fungal infections compared to those without SPM (P all < 0.05). Cytomegalovirus (CMV) and fungal infections were identified to be independent risk factors for SPM development in the anti-MDA5+ DM. SPM and non-SPM patients in our anti-MDA5+ DM cohort showed comparable short-term and long-term survival (P = 0.236). Furthermore, in the SPM group, we found that the non-survivors had a lower peripheral lymphocyte count, higher LDH level, and higher frequency of intensification of immunosuppressive treatment (IST) than survivors. The elevated LDH level and intensification of IST were independent risk factors for increased mortality in anti-MDA5+ DM-associated SPM patients. CONCLUSIONS: Nearly one-tenth of patients with anti-MDA5+ DM develop SPM. Both CMV and fungal infections are risk factors for SPM occurrence. The development of SPM does not worsen the prognosis of anti-MDA5+ DM patients, and the intensification of IST does harm to the SPM prognosis.

Anti-Toxoplasma gondii antibodies as a risk factor for the prevalence and severity of systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the presence of numerous autoantibodies. The interaction of infectious agents (viruses, bacteria and parasites) and a genetically susceptible host may be a key mechanism for SLE. Toxoplasma gondii is a widespread intracellular parasite that has been implicated in the pathogenesis of autoimmune diseases. However, the relationship between T. gondii infection and the increased risk of SLE in Chinese populations remains unclear. METHODS: The seroprevalence of T. gondii infection was assessed in 1771 serum samples collected from Chinese individuals (908 healthy controls and 863 SLE patients) from different regions of China using an enzyme-linked immunosorbent assay. Serum autoantibodies and clinical information were obtained and analysed. RESULTS: Our observations revealed a higher prevalence of anti-T. gondii antibodies (ATxA) immunoglobulin G (IgG) in serum samples from SLE patients (144/863, 16.7%) than in those from the healthy controls (53/917, 5.8%; P < 0.0001), indicating a 2.48-fold increased risk of SLE in the ATxA-IgG+ population, after adjustment for age and sex (95% confidence interval [CI] 1.70-3.62, P < 0.0001). ATxA-IgG+ SLE patients also showed a 1.75-fold higher risk of developing moderate and severe lupus symptoms (95% CI 1.14-2.70, P = 0.011) compared to ATxA-IgG- patients. Relative to ATxA-IgG- patients, ATxA-IgG+ patients were more likely to develop specific clinical symptoms, including discoid rash, oral ulcer, myalgia and alopecia. Seven antibodies, namely anti-ribosomal RNA protein (rRNP), anti-double stranded DNA (dsDNA), anti-cell membrane DNA (cmDNA), anti-scleroderma-70 (Scl-70), anti-cardiolipin (CL), anti-beta2-glycoprotein-I (B2GPI) and rheumatoid factor (RF), occurred more frequently in ATxA-IgG+ patients. When combined with anti-dsDNA and RF/anti-rRNP/anti-cmDNA/ESR, ATxA-IgG significantly increased the risk for severe lupus. CONCLUSIONS: Our results suggest that ATxA-IgG may be a significant risk factor for SLE prevalence and severity in Chinese populations.

Differential Gene Expression and Immune Cell Infiltration in Patients with Steroid-induced Necrosis of the Femoral Head.

OBJECTIVE: The study aimed to study the differential gene expression and immune cell infiltration in patients with steroid-induced necrosis of the femoral head (SANFH), identify the key genes and immune cells of SANFH, and explore the relationship between immune cells and SANFH. METHODS: The high-throughput gene chip dataset GSE123568 was downloaded from the GEO database, and the differential gene expression was analyzed with the R language. The STRING database and Cytoscape software were used to analyze the protein interaction network and screen key genes, and enrichment analysis was carried out on key genes. The infiltration of immune cells in SANFH patients was analyzed and verified by immunohistochemistry. RESULTS: EP300, TRAF6, STAT1, JAK1, CASP8, and JAK2 are key genes in the pathogenesis of SANFH, which mainly involve myeloid cell differentiation, cytokine-mediated signaling pathway, tumor necrosis factor-mediated signaling pathway, and cellular response to tumor necrosis factor through JAK-STAT, NOD-like receptor, toll-like receptor, and other signaling pathways, leading to the occurrence of diseases; immune infiltration and immunohistochemical results have shown the expression of memory B cells and activated dendritic cells as reduced in SANFH patients, while in the same SANFH samples, M1 macrophages have been positively correlated with monocytes, and neutrophils have been negatively correlated with monocytes expression. CONCLUSION: EP300, TRAF6, STAT1, JAK1, CASP8, and JAK2 have exhibited significant differences in SANFH (spontaneous osteonecrosis of the femoral head). Memory B cells, activated dendritic cells, M1 macrophages, monocytes, and neutrophils have shown abnormal expression in SANFH.

Anti-MDA5 antibody-positive dermatomyositis: pathogenesis and clinical progress.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis. Although the aetiology and pathology remain unclear, increasing evidence suggests that viral infection is a potential trigger of MDA5-DM. Multiple factors, including T cells, B cells, neutrophils and macrophages, are implicated in the pathophysiology of MDA5-DM. Distinctive skin rashes, rapidly progressive interstitial lung disease, peripheral lymphopenia and elevated serum ferritin levels are the most prominent clinical and laboratory features of MDA5-DM. Concomitant infection is a common complication of MDA5-DM. The proper evaluation of patients with MDA5-DM requires knowledge of the disease heterogeneity and clinical course variability. Several biomarkers, including serum levels of anti-MDA5 antibodies and biomarkers related to macrophage activation, have been identified as useful tools for monitoring disease activity and prognosis. MDA5-DM shows a poor response to conventional glucocorticoid and immunosuppressant therapy and has a poor overall prognosis. Therefore, there is an urgent need to explore the key pathogenic mechanisms of MDA5-DM and develop novel therapeutic options for patients. This Review discusses recent clinical progress and pathogenic findings of MDA5-DM.

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.

Upregulation of the CD155-CD226 Axis Is Associated With Muscle Inflammation and Disease Severity in Idiopathic Inflammatory Myopathies.

BACKGROUND AND OBJECTIVES: The CD155-CD226/T-cell Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) pathway plays a critical role in regulating T-cell responses and is being targeted clinically. However, research on the role of this pathway in autoimmune diseases is limited. This study aimed to investigate the expression and tissue-specific roles of CD155-CD226/TIGIT pathway molecules in the inflamed muscles of patients with idiopathic inflammatory myopathies (IIMs). METHODS: Immunohistochemistry, Western blot analysis, and polychromatic immunofluorescence staining were performed to examine the expression of CD155, CD226, and TIGIT in skeletal muscle biopsies from 30 patients with dermatomyositis (DM), 10 patients with amyopathic DM (ADM), 20 patients with immune-mediated necrotizing myopathy (IMNM), 5 patients with dysferlinopathy, and 4 healthy controls. Flow cytometry analysis was used to analyze the functions of T cells with different phenotypes. RESULTS: Strong expression of CD155 was observed in patients with DM and IMNM, while its expression was largely negative in those with ADM and dysferlinopathy and healthy controls. The costimulatory receptor CD226 was highly expressed on muscle-infiltrating cells, while the coinhibitory receptor TIGIT was expressed at low levels. These infiltrating CD226+ cells were mainly activated effector T cells that localized adjacent to CD155-expressing myofibers, but were faintly detectable within the muscle fascicles lacking CD155. A strong positive correlation between CD155 and CD226 expression scores was also observed. Polychromatic immunofluorescence staining revealed that CD155+ muscle cells coexpressed major histocompatibility complex classes I and II, and tumor necrosis factor alpha expression was detected in CD226+ T cells at their close sites with the myofibers. Furthermore, the expression levels of CD155 and CD226 showed a positive correlation with creatine kinase, lactate dehydrogenase, and the muscle histopathology damage scores and an inverse correlation with the Manual Muscle Testing-8 scores. In addition, CD155 and CD226 expressions were significantly decreased in representative patients who achieved remission posttreatment. DISCUSSION: These findings demonstrate that the CD155-CD226 axis is highly activated in inflamed muscle tissues of patients with IIM and is associated with muscle disease severity. Our data uncover the immunopathogenic role of the axis in the pathology of IIMs.

Clinical, radiological and pathological features of anti-MDA5 antibody-associated interstitial lung disease.

INTRODUCTION: To investigate the clinical, radiographic and pathological features of interstitial lung disease (ILD) in patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (anti-MDA5+DM). METHODS: We retrospectively analysed the medical records of patients with anti-MDA5+DM who had undergone radiological examination, and lung histopathology was performed on 17 of them. RESULTS: This study examined 329 patients with anti-MDA5+DM, of whom 308 (93.6%) were diagnosed with ILD and 177 (53.8%) exhibited rapidly progressive ILD (RPILD). The most common radiographic patterns were organising pneumonia (OP) (43.2%), non-specific interstitial pneumonia (NSIP) (26.4%) and NSIP+OP (18.5%). Histological analysis showed NSIP (41.2%) and NSIP+OP (47.1%) to be the predominant patterns. However, in the 17 patients who underwent lung histopathology, the coincidence rate between radiological and histopathological diagnoses was only 11.8%. Compared with patients without RPILD, those with RPILD showed a higher prevalence of NSIP+OP (26.6% vs 10.7%, p=0.001) and a lower prevalence of NSIP pattern (21.5% vs 37.4%, p=0.002) on high-resolution CT. Furthermore, patients with radiographic patterns of NSIP+OP or diffuse alveolar damage (DAD) had more risk factors for poor prognosis, with 12-month mortality rates of 45.9% and 100%, respectively. CONCLUSIONS: RPILD was commonly observed in patients with anti-MDA5+DM. OP was identified as the predominant radiographic pattern, which corresponded to a histopathological pattern of NSIP or NSIP+OP. Notably, patients exhibiting radiographic patterns of NSIP+OP or DAD were shown to have a poor prognosis.

Decrease in cell counts and alteration of phenotype characterize peripheral NK cells of patients with anti-MDA5-positive dermatomyositis.

OBJECTIVE: To investigate the levels and phenotypes of peripheral natural killer (NK) cells in anti-MDA5+ dermatomyositis (DM) patients, and their association with clinical features. METHODS: Peripheral NK cell counts (NKCCs) were retrospectively collected from 497 patients with idiopathic inflammatory myopathies and 60 healthy controls. Multi-color flow cytometry was used to determine the NK cell phenotypes in additional 48 DM patients and 26 healthy controls. The association of NKCC and NK cell phenotypes with the clinical features and prognosis were analyzed in anti-MDA5+ DM patients. RESULTS: NKCC was significantly lower in anti-MDA5+ DM patients than in those with other IIM subtypes and healthy controls. A significant decrease in NKCC was associated with disease activity. Furthermore, NKCC < 27 cells/µL was an independent risk factor for 6-month mortality in anti-MDA5+ DM patients. In addition, identification of the functional phenotype of NK cells revealed significantly increased expression of the inhibitory marker CD39 in CD56brightCD16dimNK cells of anti-MDA5+ DM patients. CD39+NK cells of anti-MDA5+ DM patients showed increased expression of NKG2A, NKG2D, Ki-67, decreased expression of Tim-3, LAG-3, CD25, CD107a, and reduced TNF-α production. CONCLUSION: Decreased cell counts and inhibitory phenotype are significant characteristics of peripheral NK cells in anti-MDA5+ DM patients.

Immunoproteasome subunit ß5i promotes perifascicular muscle atrophy in dermatomyositis by upregulating RIG-I.

BACKGROUND: Perifascicular atrophy is a unique pathological hallmark in dermatomyositis (DM)-affected muscles; however, the mechanism underlying this process remains unclear. In this study, we aimed to investigate the potential role of the immunoproteasome subunit ß5i and retinoic acid-inducible gene-I (RIG-I) in DM-associated muscle atrophy. METHODS: The expression of ß5i and RIG-I in the muscles of 16 patients with DM was examined by PCR, western blotting and immunohistochemistry. The associations between ß5i and RIG-I expression levels and muscle disease severity were evaluated. Lentivirus transduction was used to overexpress ß5i in human skeletal muscle myoblasts (HSMMs) and consequent cell functional changes were studied in vitro. RESULTS: ß5i and RIG-I expression in the muscle of patients with DM was significantly increased and closely associated with muscle disease severity. Immunohistochemistry and immunofluorescence analyses showed the marked colocalised expression of ß5i and RIG-I in perifascicular myofibres. ß5i overexpression in HSMMs significantly upregulated RIG-I, the muscle atrophy marker MuRF1, type I IFN-related proteins (MxA and IFNß) and NF-κB pathway-related proteins (pIκBα, pIRF3 and pNF-κBp65). In addition, the viability of HSMMs decreased significantly after ß5i overexpression and was partly recovered by treatment with a ß5i inhibitor (PR957). Moreover, activation of RIG-I by pppRNA upregulated IFNß and MuRF1 and reduced the cell viability of HSMMs. CONCLUSION: The immunoproteasome subunit ß5i promotes perifascicular muscle atrophy in DM via RIG-I upregulation; our findings suggest a pathomechanistic role of ß5i and RIG-I in DM-associated muscle damage, highlighting these components as potential therapeutic targets for the treatment of DM.

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.

Long-Term Outcomes and Prognosis Factors in Patients With Idiopathic Inflammatory Myopathies Based on Myositis-Specific Autoantibodies: A Single Cohort Study.

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.

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.

The clinical features and prognoses of anti-MDA5 and anti-aminoacyl-tRNA synthetase antibody double-positive dermatomyositis patients.

Objective: To explore the clinical features and prognoses of dermatomyositis (DM) associated with a double-positive anti-MDA5 and anti-aminoacyl-tRNA synthetase (anti-ARS) antibody presentation. Methods: We retrospectively analyzed 1280 consecutive patients with idiopathic inflammatory myopathy (IIM). Individuals with anti-MDA5 and anti-ARS antibodies (anti-MDA5+/ARS+) were compared to anti-MDA5-/ARS+ and anti-MDA5+/ARS- control individuals based on clinical, pulmonary radiological characteristics, treatment, and follow-up information. Results: Six individuals (0.47%) presented with anti-MDA5+/ARS+; of these, 2 (33.3%) were anti-PL-12+, 2 (33.3%) were anti-Jo-1+, 1 (16.7%) was anti-EJ+, and 1 (16.7%) was anti-PL-7+. Hallmark cutaneous manifestations, including Gottron's sign (100%), heliotrope rash (50%), mechanic's hand (66.7%), and skin ulcers (16.7%) were common. Anti-MDA5+/ARS+ patients tended to have higher ferritin levels (p = 0.038) than anti-MDA5-/ARS+ group, and higher CD4+ T-cell counts (p = 0.032) compared to the anti-MDA5+/ARS- group. Radiologically, NSIP with OP overlap was predominant (60%). Consolidation (60%), ground-glass attenuation (GGA) (80%), traction bronchiectasis (80%), and intralobular reticulation (100%) were common in anti-MDA5+/ARS+ individuals. All were diagnosed with ILD and 50% were categorized as RPILD. All patients received glucocorticoids combined with one or more immunosuppressants. Most (83.3%) had a good prognosis following treatment, but there was no difference in the survival rate between the three subgroups. Conclusion: Presentation with anti-MDA5+/ARS+ DM was rare. The clinical and radiological characteristics of anti-MDA5+/ARS+ DM combined the features of anti-MDA5+ and anti-ARS+ individuals. Individuals with anti-MDA5+/ARS+ antibodies may respond well to glucocorticoid therapy; glucocorticoids combined with one or more immunosuppressants may be considered a basic treatment approach.

Adrenomedullin Expression Is Associated With the Severity and Poor Prognosis of Interstitial Lung Disease in Dermatomyositis Patients.

Objective: To evaluate adrenomedullin mRNA levels in the peripheral blood mononuclear cells (PBMCs) of patients with dermatomyositis (DM) as well as their correlation with the severity of interstitial lung disease (ILD). Methods: A total of 41 DM patients and seven immune-mediated necrotizing myopathy (IMNM) patients were recruited, in addition to 21 healthy controls (HCs). The adrenomedullin mRNA levels in PBMCs were measured via quantitative reverse-transcription real-time polymerase chain reaction (qRT-PCR). The associations between adrenomedullin expression levels and major clinical, laboratory, pulmonary function parameters and the prognosis of patients with DM-related ILD (DM-ILD) were analyzed. Immunohistochemical analysis was performed on lung tissues of DM-ILD patients to determine adrenomedullin expression. Results: Adrenomedullin mRNA levels in PBMCs were significantly higher in DM patients than in IMNM patients and HCs (p = 0.022 and p<0.001, respectively). Among DM patients, the levels were significantly higher in those with rapidly progressive ILD (RP-ILD) than in those with chronic ILD (p = 0.002) or without ILD (p < 0.001). The adrenomedullin mRNA levels in DM-ILD were positively correlated with serum ferritin (r =0.507, p =0.002), lactate dehydrogenase (LDH) (r =0.350, p =0.045), and lung visual analog scale (VAS) (r=0.392, p=0.021) and were negatively correlated with pulmonary function test parameters, including predicted forced vital capacity (FVC)% (r = -0.523, p = 0.025), forced expiratory volume in 1 s (FEV1)% (r = -0.539, p = 0.020), and diffusing capacity of carbon monoxide (DLco)% (r = -0.495, p = 0.036). Immunohistochemical analysis of adrenomedullin confirmed higher expression in the alveolar epithelial cells and macrophages of DM patients with RP-ILD. Among the DM patients with ILD, the six decedents exhibited higher adrenomedullin levels than the 28 survivors (p = 0.042). The cumulative survival rate was significantly lower (62.5% vs. 100%, P = 0.005) in patients with an adrenomedullin level > 0.053 than in those with a level <0.053. Conclusions: Adrenomedullin levels are upregulated in DM patients with RP-ILD and are associated with ILD severity and poor prognosis. Adrenomedullin may be a potential prognostic biomarker in DM patients with ILD, although need further investigation.

Resistin Expression Is Associated With Interstitial Lung Disease in Dermatomyositis.

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.