Anti-melanoma Differentiation-associated Protein Research Articles

Low serum complements in idiopathic inflammatory myositis: clinical features and impact on the prognosis.

This study investigated the clinical features and prognostic relevance of decreased serum complement levels in patients with idiopathic inflammatory myositis (IIM). The clinical information of IIM patients with less than normal serum complement levels (L-Com) and that of those with normal serum complement levels (N-Com) was compared. In patients with interstitial lung disease (ILD), regression analyses were used to investigate the implication of L-Com in their PaO2/FiO2 (P/F) ratio. Prognostic outcomes of ILD were evaluated using the log-rank test. Of 94 IIM patients, 26 with L-Com (median age, 56.0 years) and 68 with N-Com (56.5 years) were included. The prevalence of women was significantly higher in patients with L-Com (92.3%) than in those with N-Com (67.6%). ILD was observed in 17 (65.4%) patients with L-Com and in 46 (67.6%) with N-Com. Among patients with ILD, the P/F ratio was significantly lower in those with L-Com than in those with N-Com. Serum C3 levels were correlated with decreased P/F ratio. Inferior prognosis of ILD was significantly demonstrated in patients with L-Com, especially in those positive for anti-melanoma differentiation-associated protein 5 antibody. L-Com may be implicated in reduced arterial oxygen levels and a poorer prognosis in patients with IIM-related ILD.

Prognostic significance of natural killer cell depletion in predicting progressive fibrosing interstitial lung disease in idiopathic inflammatory myopathies.

Interstitial lung disease (ILD) is one of the common extramuscular involvement in idiopathic inflammatory myopathies (IIMs) (1). Several patients develop a progressive fibrosing ILD (PF-ILD) despite conventional treatment, resulting in a progressive deterioration in their quality of life (2). Here, we investigated the clinical and immune characteristics of IIM-ILD and risk factors for PF-ILD in IIM, mainly in anti-melanoma differentiation-associated protein 5 (anti-MDA5+) dermatomyositis (DM) and anti-synthetase syndrome (ASS). Here, a prospective cohort of 156 patients with IIM-ILD were included in the longitudinal analysis and divided into the PF-ILD (n=65) and non-PF-ILD (n=91) groups, and their baseline clinical characteristics were compared. Univariate and multivariate Cox analyses were performed to identify the variables significantly associated with pulmonary fibrosis progression in the total cohort, then anti-MDA5+ DM and ASS groups separately. Peripheral blood lymphocyte counts, including T, B, and NK cell counts, were significantly lower in the PF-ILD group than in the non-PF-ILD group. This characteristic is also present in the comparison between patients with anti-MDA5+ DM and ASS. The multivariate Cox regression analysis revealed that age > 43.5 years [HR: 7.653 (95% CI: 2.005-29.204), p = 0.003], absolute NK cell count < 148 cells/μL [HR: 6.277 (95% CI: 1.572-25.067), p = 0.009] and absolute Th cell count < 533.2 cells/μL [HR: 4.703 (95% CI: 1.014-21.821), p = 0.048] were independent predictors of progressive fibrosing during 1-year follow-up for patients with anti-MDA5+ DM, while absolute count of NK cells < 303.3 cells/µL [HR: 19.962 (95% CI: 3.108-128.223), p = 0.002], absolute count of lymphocytes < 1.545×109/L [HR: 9.684 (95% CI: 1.063-88.186), p = 0.044], and ferritin > 259.45 ng/mL [HR: 6 (95% CI: 1.116-32.256), p = 0.037] were independent predictors of PF-ILD for patients with ASS. Patients with anti-MDA5+ DM and ASS have independent risk factors for PF-ILD. Lymphocyte depletion (particularly NK cells) was significantly associated with PF-ILD within 1-year of follow-up for IIM-ILD.

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.

The Type I Interferon Signature Reflects Multiple Phenotypic and Activity Measures in Dermatomyositis.

The type 1 interferon (IFN) pathway is up-regulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM. RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed up during the course of their clinical care. A previously defined 13-gene type I IFN score was modeled as a function of demographic, serologic, and clinical variables using both cross-sectional and longitudinal data. The pattern of type I IFN-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to systemic lupus erythematosus. The median type I IFN score was higher or lower in patients with anti-melanoma differentiation-associated protein 5 (anti-MDA-5) or anti-Mi-2 antibodies, respectively, compared to patients without these antibodies. Absolute type I IFN score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA-5 antibodies. Changes in the type I IFN score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation between changes in the type I IFN score and skin disease activity (Spearman's ρ=0.84-0.95). The type I IFN score is independently associated with skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA-5 status revealed that the type I IFN score is strongly correlated with skin disease activity, providing support for type I IFN blockade as a therapeutic strategy for DM.

Risk Prediction for Rapidly Progressive Interstitial Lung Disease in Anti-MDA5-Positive Dermatomyositis: The CRAFT Model.

BACKGROUND Anti-melanoma differentiation-associated protein 5-positive dermatomyositis (MDA5⁺ DM) is characterized by a life-threatening complication of rapidly progressive interstitial lung disease (RP-ILD). Early prediction of RP-ILD can enhance diagnostic accuracy and therapeutic efficacy. This study was conducted to develop a nomogram model for predicting RP-ILD in patients with MDA5⁺ DM. MATERIAL AND METHODS We retrospectively analyzed 53 patients with MDA5⁺ DM, of whom 21 patients were diagnosed with RP-ILD between January 2018 and January 2021. Univariate analysis (t test, Mann-Whitney U test, chi-squared test, or Fisher's exact test) and receiver operating characteristic (ROC) analysis were used to select candidate variables. Multivariate logistic regression analysis was conducted to construct a prediction model, which was subsequently transformed into a nomogram. ROC analysis, calibration curve and decision curve analysis were performed to evaluate the model's performance. The bootstrapping method (resampling=500) was used for internal validation. RESULTS We successfully established a nomogram, called the CRAFT model, to predict RP-ILD in MDA5⁺ DM patients. The model included 4 variables, namely C-reactive protein-to-albumin ratio, red blood cell distribution width-coefficient of variation, fever status, and CD3⁺ T cells. The model presented high predictive power and a good performance in calibration curve and decision curve analysis. In addition, the model had a good predictive ability in internal validation. CONCLUSIONS The CRAFT model could help to predict RP-ILD in patients with MDA5⁺ DM.

In-depth proteomic analysis of juvenile dermatomyositis serum reveals protein expression associated with muscle-specific autoantibodies.

The clinical symptoms and complications of juvenile dermatomyositis (JDM) differ depending on the type of muscle-specific autoantibodies (MSAs) present. We aimed to identify protein expression profiles specific for MSAs that characterize various clinical features by comprehensively analyzing the proteins present in the serum of patients with JDM. We analyzed sera from patients with JDM that were positive for anti-melanoma differentiation-associated protein 5 (MDA5) antibodies (n = 5), anti-nuclear matrix protein 2 (NXP2) antibodies (n = 5), and anti-transcriptional intermediary factor 1 alpha or gamma subunit (TIF1-γ) antibodies (n = 5) and evaluated healthy controls (n = 5) via single-shot liquid chromatography-tandem mass spectrometry (MS) in data-independent acquisition mode, which is superior for comparative quantitative analysis. We identified different protein groups based on MSAs and performed pathway analysis to understand their characteristics. We detected 2,413 proteins from serum MS analysis; 508 proteins were commonly altered in MSAs, including many myogenic enzymes and interferon-regulated proteins. Pathway analysis using the top 50 proteins that were upregulated in each MSA group revealed that the type 1 interferon and proteasome pathways were significantly upregulated in the anti-MDA5 antibody group alone. Although JDM serum contains many proteins commonly altered in MSAs, the pathways associated with clinical features of MSAs differ based on protein accumulation. In-depth serum protein profiles associated with MSAs may be useful for developing therapeutic target molecules and biomarkers.

Subsets of Idiopathic Inflammatory Myositis Enriched for Contemporaneous Cancer Relative to the General Population.

This study investigates cancer risk in idiopathic inflammatory myopathy (IIM) relative to the general population. We conducted a single-center, retrospective cohort study of IIM patients and malignancy. Myositis-specific and -associated autoantibodies were determined by Euroimmun line blot, enzyme-linked immunosorbent assay, and immunoprecipitation. We calculated standardized prevalence ratios (SPRs) and adjusted for calendar year, age, sex, race, and ethnicity by comparing observed cancers in IIM patients versus expected cancers in the general population using the Surveillance, Epidemiology, and End Results registry. Of 1,172 IIM patients, 203 (17%) patients with a cancer history were studied. Over a median follow-up of 5.2 years, the observed number of IIM patients diagnosed with cancer was increased 1.43-fold (SPR 1.43 [95% confidence interval (95% CI) 1.15-1.77]; P=0.002). Within 3 years of IIM symptom onset, an increased SPR was observed for anti-transcription intermediary factor 1γ (anti-TIF1γ)-positive patients for ovarian and breast cancer (ovarian SPR 18.39 [95% CI 5.01-47.08], P < 0.001; breast SPR 3.84 [95% CI 1.99-6.71], P < 0.001). As expected, anti-TIF1γ positivity was associated with a significantly elevated SPR; however, only 55% (36 of 66) of all cancers within 3 years of dermatomyositis onset were observed in anti-TIF1γ-positive patients. Other myositis-specific autoantibodies, including anti-Mi-2, anti-small ubiquitin-like modifier activating enzyme (SAE), and anti-nuclear matrix protein 2 (NXP-2), accounted for 26% (17 of 66) of cancers diagnosed within 3 years of dermatomyositis onset. No cancer association, positive or negative, was observed for patients with antisynthetase, anti-melanoma differentiation-associated protein 5 (anti-MDA-5), or anti-hydroxymethylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies. In a tertiary referral center population, anti-TIF1γ was most strongly associated with breast and ovarian cancer. Patients with antisynthetase, anti-MDA-5, or anti-HMGCR antibodies had the same cancer risk as the general population.

Differences in the Clinical Characteristics and 1-Year Mortality Rates of Patients with Dermatomyositis with anti-Jo-1 and anti-MDA5 Antibodies.

Patients with anti-Jo-1 antibodies (Abs) and anti-melanoma differentiation-associated protein 5 (MDA5) Abs are at a higher risk of interstitial lung disease (ILD) and have a mortality rate higher than that of patients with anti-Jo-1 Abs. This study investigated differences in the clinical characteristics and prognosis of patients with anti-Jo-1 Abs and anti-MDA5 Abs with dermatomyositis (DM). We retrospectively reviewed the medical records of 38 patients with DM from January 2000 to December 2021. The patients were divided into anti-Jo-1 Abs and anti-MDA5 Abs groups. The basic demographic data, clinical manifestations, and 1-year mortality rates of the groups were compared. Among the 38 patients, 30 were anti-Jo-1-Abs positive and 8 patients were anti-MDA5 Aba positive. The patients with anti-MDA5 Abs presented with more apparent cutaneous symptoms and aggressive pulmonary manifestations than did those with anti-Jo-1 Abs. The mortality rate in the anti-MDA5 Abs group (1.95/person-year (PY)) was much higher than that in anti-Jo-1 Abs group (0.094/PY), and most of the mortalities occurred within the first 1-3 months of follow-up. Distinct cutaneous and pulmonary manifestations were observed in the anti-Jo-1 Abs and anti-MDA5 Abs groups. The mortality rate in the anti-MDA5 Abs group was significantly higher than that in the anti-Jo-1 Abs group. Early recognition is crucial to ensuring higher chances of survival for patients with anti-MDA5 Abs.

Myositis-specific antibodies in dermatomyositis: A single-center experience of 33 cases in Taiwan

Dermatomyositis (DM) is a systemic autoimmune disease characterized by unique cutaneous manifestations and inflammatory myopathies. With the discovery of myositis-specific antibodies (MSAs), patients with DM, especially those with a higher risk of life-threatening complications, can be classified according to the MSA type. This retrospective study aimed to investigate the clinical significance of MSAs in patients with DM in Taiwan. A total of 33 patients with DM who underwent the MSA test, including 26 with classic DM and 7 with amyopathic DM, were included. There were 13 men and 20 women, with a mean age at diagnosis of 49.6 years. MSA was detected in 26 (78.8%) of 33 patients with DM. The most frequently detected MSA was anti-melanoma differentiation-associated protein 5 (MDA5) (10/33, 30.3%) followed by anti-transcription intermediary factor-1γ (TIF-1γ) (8/33, 24.2%). Dysphagia was present in 6 (18.2%) of the 33 patients and more frequently developed in patients with anti-TIF-1γ (+) (5/8, 62.5%) than those with anti-TIF-1γ (−) (1/25, 4.0%). Interstitial lung disease was noted in 15 patients (45.5%) and developed more frequently in patients with anti-MDA5 (+) (7/10, 70.0%) than those with anti-MDA5 (−) (8/23, 34.8%). Malignancies were detected in 4 (12.1%) patients, with one each of anti-Mi-2 (+), anti-TIF-1γ (+), anti-ARS (+), and MSA (−). Mortality occurred in 6 (18.2%) patients, of whom 4 were anti-MDA5 (+). Anti-MDA5 and anti-TIF-1γ were the two most commonly detected MSAs. The presence of specific MSAs is associated with a certain phenotype, and integrating MSAs while evaluating DM aids in accurate patient management.

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

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. 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. 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). 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.

Evaluation of the Performance of an Indirect Immunofluorescence Assay for the Detection of Anti-MDA5 Antibodies.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody (Ab) positive dermatomyositis (anti-MDA5 DM) is a rare systemic autoimmune disease; further, its prognosis can be rapidly fatal due to pulmonary involvement. The identification and quantification of anti-MDA5 Abs, which serve as a highly specific biomarker of the disease, is a critical step for the establishing of both the diagnosis and monitoring of the disease's activity. The development of a simple, fast, low-cost, and specific detection system of anti-MDA5 Ab is therefore highly desirable for the purposes of routine laboratory diagnosis. Here, we developed a human cell line that stably expresses MDA5 and evaluated its analytical performance in order to detect anti-MDA5 Abs by the utilization of indirect immunofluorescence (IIF). Serum samples from 23 anti-MDA5 DM patients and 22 anti-MDA5 Abs negative myositis readings, which were obtained at time of diagnosis, were analyzed by IIF on MDA5-transfected cells. The results were compared with those obtained with specific semi-quantitative (immunodot) and quantitative (ELISA) assays. A specific cytoplasmic pattern was found solely with the sera of anti-MDA5 DM patients. The sensitivity and specificity of IIF on MDA5-transfected cells were 96% and 100%, respectively, compared with ELISA. The anti-MDA5 Abs titers that were determined by this approach were consistent with the quantitative results obtained by ELISA. Baseline concentrations of anti-MDA5 Abs, either by ELISA or IIF, were not significantly different between surviving and deceased patients; further, they did not differ significantly according to clinical phenotypes. Overall, an IIF cell-based assay constitutes a simple, fast, and low-cost approach to identify and quantify anti-MDA5 Abs; moreover, it is as efficient as ELISA.

Two Distinct Immune Cell Signatures Predict the Clinical Outcomes in Patients With Amyopathic Dermatomyositis With Interstitial Lung Disease.

Amyopathic dermatomyositis (ADM) is a heterogeneous and life-threatening autoimmune disease with a high mortality rate. In particular, anti-melanoma differentiation-associated protein 5 antibody-positive patients are at a high risk of developing rapidly progressive interstitial lung disease (RPILD). This study was undertaken to identify immunologic signatures among patients who have ADM with ILD (ADM-ILD) and to discover the biomarkers predicting prognosis. The landscape of 42 immune cell phenotypes in the peripheral blood of 82 ADM-ILD patients and 82 age- and sex-matched healthy donors was assessed by multicolor flow cytometry. Patients were stratified using an unsupervised machine learning method (hierarchical clustering analysis) by immune cell subsets. Multiple Wilcoxon's signed rank tests and supervised machine learning methods were performed to identify important immune cell subsets. Kaplan-Meier survival analysis with log rank tests was used to create survival curves. We identified 2 distinct clusters correlating with different disease activities and clinical outcomes in ADM-ILD. Cluster 1 was enriched in the activated CD45RA+HLA-DR+CD8+ T cells with decreased CD56dim natural killer cell proportions and showed a higher prevalence of RPILD and higher mortality. In contrast, the other subgroup, cluster 2 (the nonactivated T cell-dominant cluster), displayed favorable clinical outcomes with high survival rates. Our data also revealed that immunophenotype was an independent risk factor associated with 1-year survival. Peripheral immunologic features may have the potential to stratify patients with ADM-ILD according to different disease severity and clinical outcomes, which may have implications for outcome prediction, pathogenesis study, and therapy selection.

Potential role of type I interferon/IP-10 axis in the pathogenesis of anti-MDA5 antibody-positive dermatomyositis.

Dermatomyositis (DM) patients with anti-melanoma differentiation-associated protein 5 (MDA5) antibodies are known for poor prognosis. This study was designed to identify humoral factors that are readily detectable in the disease and may reflect its activity and pathophysiology. We first quantified the serum level expression of 28 cytokines in the serum of patients with collagen vascular diseases using bead-based multiplex immunoassays. We completed these evaluations at hospital admission and followed up with three DM patients with anti-MDA5 antibodies during hospitalisation. We also performed an immunohistochemical analysis of skin samples obtained from two patients. The serum level of interferon gamma-induced protein 10 (IP-10) was significantly higher in DM patients with anti-MDA5 antibodies than in those without the antibody, decreasing drastically upon treatment. Interestingly, this time course paralleled not that of interferon (IFN)-γ, which was originally reported to be the inducer of IP-10, but that of IFN-α2. Immunohistochemical analysis revealed that most of the IP-10-positive cells were macrophages. Furthermore, monocytes stimulated with type I IFN in vitro produced IP-10 in a dose-dependent manner. IP-10 is a potentially useful disease activity marker of DM with anti-MDA5 antibodies, correlating more with IFN-α2 then IFN-γ. IP-10 released from macrophages might prompt the infiltration of macrophages themselves. Thus, the type I IFN/IP-10 axis may play a pivotal role in the pathogenesis of this intractable disease.

A Systematic Review and Metaanalysis of Predictors of Mortality in Idiopathic Inflammatory Myopathy-Associated Interstitial Lung Disease.

Idiopathic inflammatory myopathy (IIM)-associated interstitial lung disease (ILD) can range from rapidly progressive disease with high mortality to indolent disease with minimal morbidity. This systematic review and metaanalysis describe immunological, clinical, and radiographical predictors of mortality in IIM-ILD. MEDLINE and Embase database searches were completed on October 18, 2021, to identify articles providing survival data according to baseline characteristics in patients with concurrent IIM and ILD. Prognostic factors common to more than 5 papers were included in the metaanalysis using a random-effects model to report odds ratios (ORs) for binary variables and Hedges g for continuous variables. Risk of bias was assessed using the Newcastle-Ottawa Scale score and the Egger test for publication bias. From 4433 articles, 62 papers were suitable for inclusion; among these studies, 38 different variables were considered. The OR for risk of death regarding the presence of anti-melanoma differentiation-associated protein 5 (MDA5) antibodies was 6.20 (95% CI 3.58-10.71), and anti-tRNA synthetase antibodies were found to be protective (OR 0.24, 95% CI 0.14-0.41). Neither antinuclear antibodies, anti-52-kDa Ro antigen antibodies, nor SSA significantly altered mortality, nor was MDA5 titer predictive. Examples of prognostic factors that are significantly associated with mortality in this study include the following: age; male sex; acute/subacute onset; clinically amyopathic dermatomyositis; dyspnea; ulceration; fever; raised C-reactive protein, ferritin, lactate dehydrogenase, alveolar to arterial O2 (A-aO2) gradient, ground-glass opacity on high-resolution computed tomography (HRCT), and overall HRCT score; and reduced albumin, lymphocytes, ratio of partial pressure of oxygen in the arterial blood to fraction of inspired oxygen (PF ratio), percentage predicted transfer factor for carbon monoxide, and percentage predicted forced vital capacity. Baseline surfactant protein-D and Krebs von den Lungen-6 levels were not predictors of mortality. Many mortality risk factors were identified, though heterogeneity was high, with a low quality of evidence and a risk of publication bias. Studies regarding anti-MDA5 antibody-positive disease and and those from East Asia predominate, which could mask risk factors relevant to other IIM subgroups or populations.

Performance of the 2017 European Alliance of Associations for Rheumatology/American College of Rheumatology Classification Criteria in Patients With Idiopathic Inflammatory Myopathy and Anti-Melanoma Differentiation-Associated Protein 5 Positivity.

This study aimed to evaluate whether the 2017 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIMs) could appropriately classify the diagnosis in adult patients with anti-melanoma differentiation-associated protein 5 (anti-MDA-5)-positive IIM. In addition, this study sought to determine whether a status of anti-MDA-5 positivity could be incorporated into the EULAR/ACR IIM classification criteria set and whether the recently modified criteria based on the presence of myositis-specific autoantibodies (MSAs) could be used to appropriately classify the diagnosis in patients with anti-MDA-5-positive IIM. Consecutive adult patients clinically diagnosed as having anti-MDA-5-positive IIM from 10 hospitals in Hong Kong were retrospectively recruited; patient characteristics were obtained from electronic medical records. We used a commercial line blot immunoassay to detect MSAs. We also determined a proposed set of phenotypic-serologic classification criteria specific for anti-MDA-5. In the patient cohort (n=120; 31.7% with dermatomyositis, 68.3% with clinically amyopathic dermatomyositis [CADM]), the diagnosis could be classified with the EULAR/ACR criteria in 86 patients (71.7%) and with the Bohan and Peter criteria in 49 patients (40.8%). However, when combined with criteria specifically modified for CADM, the diagnosis could be classified by the Bohan and Peter criteria in 76.7% of patients. We observed that the sensitivity of the EULAR/ACR criteria could be improved to 98.3% if anti-MDA-5 antibody-positive status was considered as one of the criteria. The MSA-based criteria had 100% sensitivity. When we applied our proposed specific phenotypic-serologic criteria for the classification of patients with anti-MDA-5 antibodies, 97.5% of patients were able to be classified as having IIM. In this cohort of patients with anti-MDA-5-positive IIM, the diagnosis could not be classified by the EULAR/ACR criteria in almost 30% of patients. We suggest incorporating anti-MDA-5 antibody positivity as a criterion into existing criteria sets or developing specific criteria for patients with anti-MDA-5-positive IIM.

Altered Gut Microbiome in Patients With Dermatomyositis.

ObjectiveThe study objective was to compare the microbial composition of patients with dermatomyositis (DM) and healthy controls (HCs) and determine whether microbial alterations are associated with clinical manifestations of DM.MethodsThe 16S ribosomal RNA gene sequencing was performed on fecal samples from patients with DM and HCs. Microbial composition and diversity were compared between subjects with DM and HCs and in association with several DM‐specific clinical variables, including myositis‐specific autoantibodies (MSAs). Differentially abundant microbial taxa and genes associated with clinical characteristics were identified, and functional analysis was performed using predicted metagenomics. Dietary intake was assessed using a 24‐hour dietary recall.ResultsThe fecal microbiome of 36 patients with DM and 26 HCs were analyzed. Patients with DM trended toward lower microbial diversity compared with HCs. The higher physician global damage score was significantly correlated with the lower microbial diversity in patients with DM. Patients with interstitial lung disease (ILD)‐associated MSA (antisynthetase antibody (ab), anti‐melanoma differentiation‐associated protein 5 ab, n = 12) had significant differences in microbial composition and lower microbial diversity compared with HCs. Differential abundance testing demonstrated a unique taxonomic signature in the ILD‐MSA subgroup, and predictive metagenomics identified functional alterations in a number of metabolic pathways. A significant increase in the relative abundance of Proteobacteria was positively correlated with multiple pathways involved in lipopolysaccharide synthesis and transport in the ILD‐MSA group.ConclusionPatients with DM, particularly with ILD‐associated MSAs, have lower microbial diversity and a distinct taxonomic composition compared with HCs. Further studies are needed to validate our findings and elucidate specific pathogenetic mechanisms that link the gut microbiome to clinical and pathological features of DM.

POS0841 HIGH-INTENSITY INDUCTION THERAPY COMBINING TOFACITINIB, RITUXIMAB, AND PLASMAPHERESIS IN RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE ASSOCIATED WITH ANTI-MDA5 ANTIBODY POSITIVE DERMATOMYOSITIS

BackgroundRapidly progressive interstitial lung disease (RP-ILD) associated with anti-melanoma differentiation-associated protein 5 (MDA5) autoantibody (Ab) -positive dermatomyositis (DM) is one of the most life-threatening autoimmune conditions. The clinical course is very rapid, leading to death within three months after the onset of symptoms. Although triple therapy which consists of corticosteroids, cyclophosphamide, and tacrolimus has been considered as standard therapy and additional treatments including plasma exchange (PE) and rituximab (RTX) have been reported, the survival rate of patients with poor prognostic factors is still poor even if all of these treatments were applied. Recently, there exist increasing evidences regarding the efficacy of tofacitinib (TOF) in refractory DM. We have treated anti-MDA5Ab-positive RP-ILD with multiple poor prognostic factors with high-intensity induction therapy which combined triple therapy, PE, RTX, and TOF.ObjectivesThis study aimed to investigate the therapeutic efficacy of high-intensity induction therapy for patients with anti-MDA5Ab-positive RP-ILD with multiple poor prognostic factors.Methods31 patients who were diagnosed with anti-MDA5Ab-positive DM during 2014 to 2021 in our institution were included in this study. The clinical characteristics for poor prognosis were retrospectively analyzed, and the outcomes of high-intensity induction therapy were analyzed for the survival and adverse events.Results17 cases were treated before the introduction of TOF. Although triple therapy with RTX, PE, or intravenous immunoglobulin (IVIG) were used, eight out of 10 RP-ILD cases with a ferritin level &gt;400 ng/mL (range, 402.5-5,831; mean, 2,342 ± 2,069) died in median 2.5 months. Poor prognosis was predicted by followings; elevated levels of serum ferritin, lactate dehydrogenase, transaminases, creatinine phosphokinase, and C-reactive protein; decrease in platelets, serum albumin, and oxygen saturation; use of oxygen; higher age; shorter disease duration to admission. The addition of RTX and PE was not enough to control RP-ILD in anti-MDA5Ab positive DM, and prevention of the initial exacerbation of ILD following induction therapy was considered to be important. Based on these observations, high-intensity induction therapy was consisted as follows; triple therapy with decreasing the dose of methylprednisolone by half from 1g to 1 mg/kg, liposteroid to suppress macrophage activity, TOF, PE, and RTX. High-intensity induction therapy was applied in eight patients (ferritin levels; range, 412.2-7,095 ng/mL; mean, 3,558±3,152 ng/mL) with multiple poor prognostic factors described above. Although deaths at two months and eight months due to ILD were observed, significant improvement of survival was documented (Figure 1). Two patients in whom RTX was not initially administered, exacerbation of ILD was observed one month later, which prompted the use of RTX. Several adverse events were observed in high-intensity induction therapy. The most common events were reactivation of cytomegalovirus, meanwhile herpes zoster was not documented. Sustained leukocytopenia and thrombocytopenia were observed in three patients, and two patients developed thrombotic microangiopathy which led to the discontinuation of tacrolimus. Fungal infections in lung were also documented. These adverse events were controllable.Figure 1.ConclusionSignificant improvement of survival was observed in patients treated with high-intensity induction therapy. Meanwhile, stratification of patients for poor prognosis would be important.ReferencesNoneDisclosure of InterestsNone declared

Different Multivariable Risk Factors for Rapid Progressive Interstitial Lung Disease in Anti-MDA5 Positive Dermatomyositis and Anti-Synthetase Syndrome.

BackgroundInterstitial lung disease (ILD) is frequently observed in anti-melanoma differentiation-associated protein 5 (MDA5) antibody positive dermatomyositis (DM) and anti-synthetase syndrome (ASS), where they often develop a rapidly progressive ILD (RP-ILD) leading to poor prognosis.ObjectiveThe aim of this study was to construct multivariable prediction risk factors for rapid progressive ILD (RP-ILD) in anti-MDA5 positive DM (MDA5+DM) and ASS.Methods333 idiopathic inflammatory myopathy (IIM) associated ILD patients were studied retrospectively. Risk factors for RP-ILD in MDA5+DM and ASS patients were identified by univariate and multivariable logistic regression analysis. The mortality was assessed using Kaplan-Meier analysis.ResultsRP-ILD was more prevalent in MDA5+DM patients than ASS patients. MDA5+DM patients with RP-ILD had significantly lower survival rates than those in ASS patients. The independent risk factors for RP-ILD in MDA5+DM patients were fever (OR 3.67, 95% CI:1.79-7.52), lymphopenia (OR 2.14, 95% CI:1.01-4.53), especially decreased levels of CD3+T cells (OR 2.56, 95% CI:1.17-5.61), decreased levels of CD3+CD4+ T cells (OR 2.80, 95% CI:1.37-5.73), CD3+CD8+T cells (OR 2.18, 95% CI:1.05-4.50), elevated CD5-CD19+ B cells (OR 3.17, 95% CI:1.41-7.13), elevated ALT (OR 2.36, 95% CI:1.15-4.81), high lactate dehydrogenase (LDH) (OR 3.08, 95% CI:1.52-6.27), hyper-ferritin (OR 4.97, 95% CI:1.97-12.50), elevated CEA (OR 2.28, 95% CI:1.13-4.59), and elevated CA153 (OR 3.31, 95% CI:1.50-7.27). While the independent risk factors for RP-ILD in ASS patients were elevated CEA (OR 5.25, 95% CI: 1.73-15.93), CA125 (OR 2.79, 95% CI: 1.10-7.11) and NSE (OR 4.86, 95% CI: 1.44-16.37). Importantly, serum ferritin>2200ng/ml predicted patient’s death within half a year in MDA5+DM patients with RP-ILD, but not in ASS patients.ConclusionsThere were significant different mortality and multivariable risk factors for RP-ILD in MDA5+DM patients and ASS patients. Potential clinical benefits of using these different risk factors deserve assessment of severity and prognosis in IIM patients.

Serum Krebs von den Lungen-6 concentrations reflect severity of anti-melanoma differentiation-associated protein 5 antibody positive dermatomyositis associated interstitial lung disease.

Rapidly progressive interstitial lung disease (RP-ILD) is a major complication of anti-melanoma differentiation-associated protein 5 antibody positive dermatomyositis (anti-MDA5+DM) with a high mortality rate. The aim of the study is to determine whether serum Krebs von den Lungen-6 (KL-6) could be a prognostic biomarker to predict RP-ILD and prognosis in anti-MDA5+DM patients. A total of 21 anti-MDA5+DM patients with RP-ILD and 20 anti-MDA5+DM patients without RP-ILD were retrospectively included in this study. Serum KL-6 concentration (pg/mL) was measured using the latex agglutination test. Serum KL-6 level was higher in RP-ILD patients than those in non-RR-ILD patients (1195.61±872.93 vs. 452.6±465.51 pg/mL, p=0.002). The best cut-off value of KL-6 serum level was 500.9 pg/mL using ROC curve (AUC area = 0.7976, p=0.0011). KL-6 >500.9 pg/mL was an independent risk factor for RP-ILD using multivariate analysis (OR=56.38, 95% CI 5.51-577.504, p=0.001). Serum KL-6 concentrations were significantly higher in dead patients than those in the survivor group (1209.34±840.55 vs. 592.41±667.76, p=0.0033), and higher KL-6 concentration was also an independent risk factor for all-cause death after adjusting confounders (OR = 21.94, 95% CI 3.3-145.73, p=0.001). Anti-MDA5+DM patients with higher KL-6 level displayed a significantly decreased one-year survival rate, as compared with lower KL-6 level (36.36% vs. 89.47%, p=0.0008). The serum KL-6 levels reflect severity of lung injury and serve as a clinically useful biomarker in detection and monitoring RP-ILD progression in anti-MDA5+DM patients.

A novel model of dermatomyositis induced by membrane antigen and calciphylaxis in rats.

Dermatomyositis (DM) is a severe autoimmune disease of the connective tissue characterized by inflammatory and degenerative changes in the skin and muscle. However, the lack of experimental models of DM represents a challenge for the development of effective drugs. The aim of the present study was to establish a pharmacodynamic rat model of DM that would recapitulate the clinical manifestation seen in patients. The DM model was established using membrane antigen-induced autoimmune injury, followed by toxin-induced subcutaneous calciphylaxis. The rats were divided into five groups and were subcutaneously injected with membrane antigen. Of these, four antigen-immunized groups then received dihydrotestosterone (DHT), iron-dextrin (Fe-Dex), polymyxin (PMX) either individually or in combination to induce cutaneous calciphylaxis. The clinical manifestation score, ratio of infiltrated lymphocytes, ratio of arteriole calcified nodules in skeletal muscles, serum antibody levels [anti-histidyl tRNA synthetase (Jo-1) and anti-melanoma differentiation-associated protein 5 (MDA5)] and serum cytokine levels [tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)] were then detected. The results demonstrated that all five autoimmune groups displayed local cutaneous swelling and weakness, increased serum antibody and cytokine levels, and T lymphocyte infiltration in perimysial and perivascular sites. Moreover, pathological changes indicative of calciphylaxis were observed in the PMX and DHT + Fe-Dex + PMX. Among all groups, the rats in the PMX and DHT + Fe-Dex + PMX displayed characteristics most closely resembling those of DM pathogenesis in patients. In conclusion, membrane antigen immunization combined with toxin-induced calciphylaxis can be used as a DM model in rats. This model may be used for the development of effective drugs for DM treatment.