Liver Involvement is Associated with Higher Risk of Rapidly Progressive Interstitial Lung Disease and Mortality in Anti-Melanoma Differentiation-Associated Gene 5 Antibody- Positive Dermatomyositis.

Purpose: This study aimed to assess liver involvement and investigate its correlation with rapidly progressive interstitial lung disease (RP-ILD) and mortality in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5 positive) DM patients. Patients and Methods: This retrospective study included 159 patients diagnosed with anti-MDA5 positive DM or anti-synthetase syndrome (ASyS). Clinical features and laboratory findings were compared between patients with anti-MDA5 positive DM and patients with ASyS. In the anti-MDA5 positive DM cohort, clinical features and laboratory findings between patients with liver involvement and without liver involvement were further compared. The effects of liver involvement on the overall survival (OS) and development of RP-ILD were also analyzed using Kaplan-Meier method and Cox regression analysis. Results: Levels of serum aspartate aminotransferase (AST), alanine transaminase (ALT), γ-glutamyl transferase (γGT) and alkaline phosphatase (ALP) were all significantly higher in patients with anti-MDA5 positive DM than those in patients with ASyS. In our cohort of anti-MDA5 positive DM patents, 31 patients (34.4%) were complicated with liver involvement. Survival analysis revealed that serum ferritin >1030.0 ng/mL (p<0.001), ALT >103.0 U/l (p<0.001), AST >49.0 U/l (p<0.001), γGT >82.0 U/l (p<0.001), ALP >133.0 U/l (p<0.001), lactate dehydrogenase (LDH)>474.0 U/l (p<0.001), plasma albumin (ALB) <35.7 g/l (p<0.001) and direct bilirubin (DBIL) >2.80 µmol/l (p=0.002) predicted poor prognosis. The incidence of RP-ILD increased remarkably in patients with liver involvement compared to patients without liver involvement (58.1% vs 22.0%, p=0.001). Multivariate analysis revealed that elevated serum ALT level was an independent risk factor for mortality (HR 6.0, 95% CI 2.3, 16.2, p<0.001) and RP-ILD (HR 5.9, 95% CI 2.2, 15.9, p<0.001) in anti-MDA5 positive DM patents. Conclusion: Liver involvement is common in patients with anti-MDA5 positive DM. Elevated serum ALT level was an independent risk factor for RP-ILD and mortality in patients with anti-MDA5 positive DM.

Short-term and long-term outcomes of patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis characterized by frequent interstitial lung disease and reduced muscle involvement. This study aimed to determine the short-term and long-term outcomes of patients with MDA5-DM. METHODS: Information on baseline characteristics, treatments, and short-term and long-term outcomes of patients with MDA5-DM including survival, relapse, and the titer of anti-MDA5 antibody, was retrospectively collected. Descriptive statistics regarding clinical outcomes were calculated, and a comparison of clinical parameters between patients with and without relapse was performed. The short-term survival according to the use of Janus kinase inhibitors (JAKi) was also assessed. RESULTS: A total of 154 patients with MDA5-DM were included in the study. Forty patients (25.9%) died during the remission induction phase, with respiratory failure being the most common cause of mortality. Among the 114 patients who survived the remission induction phase, the 5-year cumulative survival and relapse-free survival rates were 96.8% and 77.4%, respectively, and 7.9% of patients achieved complete drug-free remission. Fifty-four patients achieved normalization of anti-MDA5 antibody titers and only two of them relapsed after normalization. In the severe patients, the 6-month survival rate became significantly higher after the emergence of the JAKi treatment compared with before its existence (p= 0.03). CONCLUSIONS: Although relapse often occurs, the long-term survival of MDA5-DM patients who survived the remission induction phase is generally favorable. The status of the anti-MDA5 antibody is associated with relapse. JAKi may improve the survival of refractory patients with severe MDA5-DM.

Correlation between B cell epitope profile and clinical features of anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (MDA5+) dermatomyositis patients exhibit a variety of clinical features. We therefore investigated whether patterns of B cell epitope recognition are linked to the clinical course of MDA5+ dermatomyositis. METHODS: Our cross-sectional study used ELISA-based methods to determine the relationship between antibody recognition of overlapping 155 amino acid MDA5 subfragments and clinical features of 24 MDA5+ myositis patients. Correlations between clinical features and standardized anti-MDA5 subfragment antibody titers were assessed via Spearman's rank correlation coefficients. RESULTS: Twenty-four MDA5+ patients submitted serum samples within a median of 0 (interquartile range, 0-74) days from the initial clinic visit. In addition to typical dermatomyositis rashes, these patients exhibited muscle symptoms (n = 11), vascular dysfunction (n = 9), and interstitial lung disease (ILD) (n = 16). Female patients exhibited higher titers of antibodies recognizing fragment H (aa 905-1026) compared to male patients. Muscle involvement was associated with higher levels of anti-fragment F (aa 646-801) antibody. Conversely, patients with vascular abnormalities had higher anti-fragment B (aa 130-284) and E (aa 517-671) antibody titers than those without vascular dysfunction. Four patients died due to ILD progression and showed higher anti-fragment A (aa 1-155) antibody titers than the other 20 patients. Differences in the ratio of anti-fragment to anti-full length MDA5 antibody titers were found for sex (H: anti-MDA5) and vascular dysfunction (anti-fragment B, E: anti-MDA5). CONCLUSIONS: Various clinical features of MDA5+ dermatomyositis correlated with levels of antibodies targeting selected subfragments of this autoantigen, providing a link between fragment-specific immune responses and disease course.

Plasma exchange for anti-MDA5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung disease: A case report and literature review.

The prognosis of anti-MDA5-positive dermatomyositis (DM)-associated rapidly progressive interstitial lung disease (RPILD) is extremely poor and effective treatment options are limited. In addition, the risk of infection during immunosuppressive treatment is a major challenge. We report here, a case of RPILD in a 31-year-old man with anti-MDA5 antibody-positive DM. Despite treatment with methylprednisolone and human immunoglobulin, his lung condition worsened and his serum ferritin levels increased. Six cycles of plasma exchange (PE) adjuvant treatment significantly mitigated his symptoms and he was discharged from hospital two months later. We suggest that PE may be a promising therapeutic option for patients with anti-MDA5-positive DM-associated RPILD. However, randomized, controlled studies are required to confirm our findings.

Treatment of refractory anti-melanoma differentiation-associated gene 5 anbibody-positive dermatomyositis complicated by rapidly progressing interstitial pulmonary disease: Two case reports.

BACKGROUND: Anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5 Ab+) dermatomyositis complicated with rapidly progressive interstitial lung disease (anti-MDA5 Ab+ DM-RP-ILD) has an unclear underlying mechanism with no recommended unified treatment plan. Herein, one of the cases that we report (Case 2) was successfully treated with tocilizumab despite having lung infection. CASE SUMMARY: Case 1 was a 30-year-old woman who was admitted due to recurrent rash for 5 mo, fever and cough for 1 mo, and chest tightness for 3 d. She was diagnosed with non-myopathic dermatomyositis (anti-MDA5 Ab+) and interstitial pneumonia, and was treated with the combination of hormone therapy and cyclophosphamide followed by oral tacrolimus. Case 2 was a 31-year-old man admitted due to systemic rash accompanied by muscle weakness of limbs for more than 1 mo, and chest tightness and dry cough for 4 d. He was diagnosed with dermatomyositis (anti-MDA5 Ab+) and acute interstitial pneumonia with Pneumocystis jirovecii and Aspergillus fumigatus infections and was treated with hormone therapy (without cyclophosphamide) and the combination of tocilizumab and tacrolimus. The condition of both patients eventually improved and they were discharged and showed clinically stable condition at the latest follow-up. CONCLUSION: Tocilizumab could be a salvage treatment for patients with anti-MDA5 Ab+ DM-RP-ILD who are refractory to intensive immunosuppression.

[Risk Factors of Rapidly Progressive Interstitial Lung Disease in Patients With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis].

Objective: To investigate the conditions of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis combined with rapidly progressive interstitial lung disease (RPILD), and to analyze the risk factors. Methods: A total of 145 patients diagnosed with anti-MDA5 antibody-positive dermatomyositis at West China Hospital, Sichuan University between January 2018 and September 2021 were selected, and their general and clinical data were collected. The patients were divided into two groups, a RPILD group of patients with comorbid RPILD and a non-RPILD group of those who did not have comorbid RPILD. Factors that might affect whether patients with anti-MDA5 antibody-positive dermatomyositis also had comorbid RPILD were screened out and binary logistic regression analysis was performed. Results: Among the 145 patients with anti-MDA5 antibody-positive dermatomyositis, 32 (22.07%) patients had comorbid RPILD, while the remaining 113 (77.93%) did not have comorbid RPILD. Binary logistic regression analysis showed that lactate dehydrogenase≥370 IU/L (compared with <370 IU/L, OR=4.066, 95% CI: 1.616-10.230) and carcinoembryo antigen≥5 ng/mL (compared with <5 ng/mL, OR=6.070, 95% CI: 2.013-18.303) were risk factors for comorbid RPILD in patients with anti-MDA5 antibody-positive dermatomyositis ( ß>0, OR>1, P<0.05). Conclusion: It is recommended that close attention be given to changes in high-resolution chest CT and pulmonary functions in patients with lactate dehydrogenase≥370 IU/L and carcinoembryo antigen≥5 ng/mL. If rapid progression of lung disease is detected, it is necessary to strengthen the treatment of the lung disease, thereby improving the prognosis of patients.

Immunosuppressive therapy before and during pregnancy may improve obstetric outcomes in pregnancy complicated by dermatomyositis with anti-MDA-5 antibody positivity: A case report.

Dermatomyositis (DM) is one of the most common autoimmune rheumatic diseases affecting women of childbearing age. Pregnancy may lead to exacerbation of DM, especially of DM with anti-melanoma differentiation-associated gene (MDA) 5 antibody positivity, leading to a poor obstetric outcome. Here, we report consecutive pregnancies complicated by DM with anti-MDA-5 antibodies. A 32-year-old pregnant woman, gravida 3 para 1, presented with fetal growth restriction. Emergency cesarean section was performed because of non-reassuring fetal status at 28 weeks of gestation. Two days postpartum, the patient's hand eczema had worsened and she was diagnosed with DM with MDA-5 antibody positivity. Immunosuppressive therapy using corticosteroids combined with tacrolimus was immediately started, suppressing the DM symptoms. Eighteen months later, she became pregnant again but was then negative for anti-MDA-5 antibodies while continuing immunosuppressive therapy. During pregnancy, the titer of the antibody gradually increased, peaked in the second trimester and declined to near normal range through the third trimester. A male infant weighing 2418 g was delivered at 38 weeks of gestation. Our case demonstrates that controlling of DM activity using immunosuppressive treatment before and during pregnancy may be beneficial to obstetric outcomes.

Cardiac involvement in anti-MDA5 dermatomyositis: a case-based review.

Among myositis-specific antibodies, anti-melanoma differentiation-associated gene 5 (anti-MDA5) is one of the antibodies with a unique spectrum that is expressed principally in clinically amyopathic dermatomyositis (CADM) and, to a lesser extent, in dermatomyositis (DM). In addition to muscle and classical skin involvement, patients with anti-MDA5 DM/CADM are characterized by the expression of rapidly progressive interstitial lung diseases, vasculopathic lesions, and non-erosive arthritis. Although cardiac involvement has been described in other inflammatory myopathies, such as myocarditis, pericarditis, and conduction disorders, in anti-MDA5 DM/CADM patients, heart disease is infrequent. We report a case of a young male presenting with constitutional symptoms, polyarthritis, skin ulcers, and mild muscle weakness who developed an episode of high ventricular rate atrial fibrillation during his hospitalization. The anti-MDA5 DM diagnosis was supported by increased muscular enzymes, positive anti-MDA5 and anti-Ro52 antibodies, and the presence of organizing pneumonia. He was treated with high-dose glucocorticoids, rituximab, and beta-blocker drugs and received pharmacological cardioversion, which improved his myopathy symptoms and stabilized his heart rhythm. Here, we describe eight similar cases of anti-MDA5 DM/CADM with cardiac involvement. The case presented and the literature reviewed reveal that although rare, physicians must be aware of cardiac disease in patients with suggestive symptoms to guarantee early assessment and treatment, thereby reducing life-treating consequences.

Relevance of leukaemia inhibitory factor to anti-melanoma differentiation-associated gene 5 antibody-positive interstitial lung disease.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive rapidly progressive interstitial lung disease (RP-ILD) is a life-threatening disease, the aetiology of which remains unclear. To detect potential diagnostic markers, a transcriptome analysis of the lung sample from a patient with anti-MDA5 antibody-positive RP-ILD was performed. METHODS: RNA sequencing analyses of an autopsy lung sample from a 74-year-old woman with anti-MDA5 antibody-positive RP-ILD was performed and compared with an age- and sex-matched normal lung sample. Genes with changes of gene expression ≥5-fold were considered differentially expressed genes and analysed by Metascape. The levels of leukaemia inhibitory factor (LIF) were measured in the serum samples from 12 cases of anti-MDA5 antibody-positive ILD, 12 cases of anti-aminoacyl tRNA synthetase (ARS) antibody-positive ILD, 10 cases of anti-transcription intermediary factor 1γ/anti-Mi-2 antibody DM and 12 healthy volunteers. RESULTS: Gene ontology enrichment analysis on the RNA sequencing data showed a strong association with antigen binding. Upregulated expressions of IL-1ß, IL-6 and LIF were also detected. Serum LIF levels were significantly elevated in anti-MDA5 antibody-positive ILD patients {median 32.4 pg/ml [interquartile range (IQR) 13.2-125.7]} when compared with anti-ARS antibody-positive ILD patients [4.9 pg/ml (IQR 3.1-19.7), P < 0.05] and DM patients [5.3 pg/ml (IQR 3.9-9.7), P < 0.05]. CONCLUSION: Our present study suggested that upregulation of LIF might be a new potential disease marker specific for anti-MDA5 antibody-positive ILD.

Successful treatment with tofacitinib for relapse of rapidly progressive interstitial lung disease in anti-melanoma differentiation-associated gene 5 antibody-positive clinically amyopathic dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is associated with clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD). Recently, several studies have reported that tofacitinib (TOF), a Janus kinase inhibitor, might be effective for cases of new or refractory RP-ILD in anti-MDA5 antibody-positive CADM; however, it is unknown whether TOF can also be effective for relapsed cases. We herein report a relapsed case of RP-ILD in anti-MDA5 antibody-positive CADM, which was successfully treated by combination therapy with TOF (5 mg twice daily). Our case suggests that TOF may also be a potential treatment option for relapsed cases of this disease.

A case of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung diseases developed after administration of COVID-19 vaccine and subsequent pneumococcal vaccine.

Five cases of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung diseases (anti-MDA5-positive DM-RPILD) following COVID-19 vaccination have been reported previously. We present the first case of the disease that developed following the sequence of COVID-19 infection, COVID-19 vaccination, and 23-valent pneumococcal polysaccharide vaccine (PPSV23) administration. A 75-year-old-Japanese man received the third dose of Pfizer COVID-19 vaccine 4 weeks after he had a mild COVID-19 infection. Eleven weeks after vaccination, he received PPSV23 for the first time. He developed fever, malaise, and anorexia the day after the PPSV23, rash a week later, and shortness of breath 2 weeks later. He was then admitted to a local hospital and treated with antibiotics, but his condition worsened. He was transferred to our hospital 4 weeks after the PPSV23 and was diagnosed with anti-MDA5-positive DM-RPILD. Despite intensive treatment, the patient died on the 10th hospital day.

Prediction model for the pretreatment evaluation of mortality risk in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease.

Background: Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease (anti-MDA5 DM-ILD) is a disease with high mortality. We sought to develop an effective and convenient prediction tool to estimate mortality risk in patients with anti-MDA5 DM-ILD and inform clinical decision-making early. Methods: This prognostic study included Asian patients with anti-MDA5 DM-ILD hospitalized at the Nanjing Drum Hospital from December 2016 to December 2020. Candidate laboratory indicators were retrospectively collected. Patients hospitalized from 2016 to 2018 were used as the discovery cohort and applied to identify the optimal predictive features using a least absolute shrinkage and selection operator (LASSO) logistic regression model. A risk score was determined based on these features and used to construct the mortality risk prediction model in combination with clinical characteristics. Results were verified in a temporal validation comprising patients treated between 2019 and 2020. The primary outcome was mortality risk within one year. The secondary outcome was overall survival. The prediction model's performance was assessed in terms of discrimination, calibration, and clinical usefulness. Results: This study included 127 patients, (72 men [56.7%]; median age, 54 years [interquartile range, 48-63 years], split into discovery (n = 87, 70%) and temporal validation (n=37, 30%) cohorts. Five optimal features were selected by LASSO logistic regression in the discovery cohort (n = 87) and used to construct a risk score, including lymphocyte counts, CD3+CD4+ T-cell counts, cytokeratin 19 fragment (CYFRA21-1), oxygenation index, and anti-Ro52 antibody. The retained predictive variables in the final prediction model were age, Heliotrope, fever, and risk score, and the most predictive factor was the risk score. The prediction model showed good discrimination (AUC: 0.915, 95% CI: 0.846-0.957), good calibration (Hosmer-Lemeshow test, P = 0.506; Brier score, 0.12), and fair clinical usefulness in the discovery cohort. The results were verified among patients in the temporal validation cohort (n = 38). We successfully divided patients into three risk groups with very different mortality rates according to the predictive score in both the discovery and validation cohorts (Cochran-Armitage test for trend, P < 0.001). Conclusions: We developed and validated a mortality risk prediction tool with good discrimination and calibration for Asian patients with anti-MDA5 DM-ILD. This tool can offer individualized mortality risk estimation and inform clinical decision-making.

Myocardial involvement is not rare in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis/clinically amyopathic dermatomyositis: a retrospective study.

Objectives: Studies concerning myocardial involvement (MI) in patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis/clinically amyopathic dermatomyositis (anti-MDA5 Ab+ DM/CADM) are scarce. We aimed to characterize MI in our anti-MDA5 Ab+ DM/CADM cohort and to investigate its association with prognosis. Methods: In this single-center retrospective study, anti-MDA5 Ab+ hospitalized DM/CADM patients who underwent transthoracic echocardiography (TTE) were enrolled. Myocardial involvement was diagnosed according to abnormal cardiac structure and function detected by TEE. Clinical features and cardiac examination findings of patients with MI were analyzed. Clinical features, laboratory findings, complications, and treatments were compared between MI and non-MI, deceased, and survival patients. Logistic regression analysis was used to explore the independent risk factors for the occurrence of MI and prognostic factors for these patients. Results: Seventy-six hospitalized patients with anti-MDA5 Ab+ DM/CADM were enrolled. Twelve (15.8%) patients were diagnosed with MI. Of the 12 patients, three underwent cardiac magnetic resonance imaging (CMR) and late gadolinium enhancement (LGE) were noted for them. TEE revealed that eight (66.7%) patients had left atrial and/or ventricular enlargement, three (25.0%) had cardiac hypertrophy, six (50.0%) had diffuse ventricular wall dyskinesia, and seven (58.3%) had diastolic dysfunction. Six (50.0%) patients with MI developed heart failure (HF) during treatment. Of the 12 patients, one patient died of HF caused by myocarditis, three died of infection, and four died of exacerbation of rapidly progressive interstitial lung disease (RP-ILD). Logistic regression analysis revealed that dysphagia (OR 3.923, 95% CI 1.085, 14.181), NT-proBNP >600 pg/ml (OR 18.333, 95% CI 1.508, 222.875), and increased peripheral white blood cells (OR 1.201, 95% CI 1.003, 1.438) were risk factors for the occurrence of MI, but plasma albumin (OR 0.892, 95% CI 0.796, 0.999) was a protective factor. Both MI (OR 5.984, 95% CI 1.174, 30.496) and RP-ILD (OR 11.875, 95% CI 2.796, 50.411) were independent risk factors for the mortality of these anti-MDA5 Ab+ DM/CADM patients. Conclusion: Myocardial involvement is not rare and is an independent poor prognostic factor of anti-MDA5 Ab+ DM/CADM patients. Cardiac abnormality screening is necessary for them.

Rapidly Progressive Interstitial Lung Disease Associated with Melanoma Differentiation-Associated Gene 5 Antibody.

Anti-melanoma differentiation-associated gene-5 (MDA-5) antibody is an autoantibody found in patients with dermatomyositis. These antibody-positive patients are clinically characterized by complications of rapidly progressive interstitial pneumonia resistant to treatment and with poor prognosis. We describe herein a patient with MDA-5 antibody-positive interstitial lung disease, which progressed rapidly to death after a period of slow progress. Recently, attention has been paid to the similarities in clinical courses and CT images between MDA-5 antibody-positive interstitial lung disease and coronavirus disease 2019 (COVID-19)-associated pneumonia. Patients with MDA-5 antibody do not always have diffuse and evenly distributed bilateral opacities at the time of first presentation. This patient had significant laterality of such opacities. It should be considered that MDA-5 antibody-positive patients with such laterality in opacities might progress rapidly. Chest physicians, dermatologists, and dermatologists need to be aware of the characteristics of the disease for optimal treatment choices.

Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis complicated with macrophage activation syndrome.

Background: Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatomyositis (DM) has low survival rate, whereas macrophage activation syndrome (MAS) is a severe and life-threatening syndrome associated with autoimmune diseases. Their coexistence is very rare. This study aimed to describe the prevalence, clinical characteristics, and outcomes of anti-MDA5 antibodies-positive DM patients complicated with MAS. Methods: In this retrospective study, we enrolled DM patients with anti-MDA5 antibodies, who were hospitalized between 2016 and 2020 and included patients diagnosed with MAS. Results: We identified four (2%) DM patients with anti-MDA5 antibodies. They were females with interstitial lung disease (ILD). The level of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and ferritin were significantly higher in the MAS group than those without MAS (p < 0.05). Patients with MAS were significantly more likely to develop a dysphagia (p = 0.012). Literature review revealed eight similar cases. Together with the present study, we identified 12 patients complicated with ILD. The median age of disease onset was 52 years with a male to female ratio of 1:6. The median duration between DM onset and MAS diagnosis was 3 months. The mortality of MAS in anti-MDA5 antibody-positive DM was 50%. Patients who died were older than those who survived (56.7 years versus 35.5 years; p = 0.015). Conclusions: MAS was rare in anti-MDA5 antibody-positive DM. The higher the level of AST, LDH, and ferritin, the greater the risk of MAS. They were associated with high mortality rates, particularly in older patients.

Quantitative CT analysis of interstitial pneumonia in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis: a single center, retrospective study.

INTRODUCTION: This study aimed to assess the utility of quantitative high-resolution computed tomography (HRCT) for determining the clinical course of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease (MDA5+ ILD). METHOD: This study retrospectively analyzed the data of 34 patients with MDA5+ ILD to determine the association between the clinical findings and extent of ILD via quantitative CT analysis at baseline and short-term follow-up. Quantified HRCT scores were evaluated as the lung severity score (LSS), percentage of opacity, and percentage of high opacity. RESULTS: Thirty-four patients underwent follow-up CT scans 35 (range: 14-78) days after diagnosis. Patients who died of rapidly progressive ILD had higher LSS (p < 0.01), percentage of opacity (p < 0.01), percentage of high opacity (p = 0.01), total ground-glass opacity score (p = 0.01), serum C-reactive protein (CRP) (p = 0.03), and alveolar-arterial oxygen difference (Aa-DO2) (p = 0.01) at follow-up than those who survived. Quantified HRCT scores correlated with serum CRP and Aa-DO2 levels at follow-up. LSS at follow-up (AUC = 0.844, p < 0.01) was the best predictor of death in MDA5+ ILD patients. Patients with an LSS of > 6.5 at follow-up had higher mortality than those with an LSS of ≤ 6.5, especially when receiving triple therapy. In multivariate analysis, an LSS of > 6.5 at follow-up was significantly associated with a poor outcome. CONCLUSIONS: Quantitative CT analysis of MDA5+ ILD is useful for the objective assessment of respiratory status and disease activity. Short-term HRCT evaluation, particularly LSS, is most important in predicting its clinical course during triple therapy. Key Points • Quantitative CT analysis plays an important role in evaluating the clinical course of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease (MDA5+ ILD). • Quantified HRCT scores, particularly lung severity score, at short-term intervals from diagnosis can help to predict prognosis after triple therapy in MDA5+ ILD.

Association of Cytomegalovirus Infection With Anti-MDA5 Antibody-Positive Dermatomyositis: A Prospective Cohort Study.

Objectives: To investigate whether cytomegalovirus (CMV) infection plays a role in the pathogenesis and prognosis of idiopathic inflammatory myopathy (IIM), particularly in anti-MDA5 antibody-positive (anti-MDA5+) dermatomyositis (DM). Methods: A prospective cohort of 204 newly diagnosed IIM patients and 50 healthy individuals were enrolled in the study. CMV-IgM and CMV-IgG antibody concentrations and lymphocyte counts were analyzed. Differences in categorical data were compared using Fisher's exact test and the chi-square test. One-year survival rates were analyzed in MDA5+ DM patients with and without CMV infection. Results: In IIM patients, the median CMV-IgM level was significantly higher than in healthy controls (6 U/mL vs. 0 U/mL, p < 0.05) as was the median CMV-IgG level (114 U/mL vs. 105 U/mL, p < 0.05). The percentage of recent CMV infections in the MDA5+ DM group was much higher than it was in the MDA5- IIM group (19.1% vs. 7.0%, p = 0.009). MDA5+ DM patients with CMV DNA-emia had poorer 1 year survival than the CMV-DNA- group (33.3% vs. 86.3%, p = 0.010). CMV-IgM-positive (CMV-IgM+) MDA5+ DM patients had lower CD4+ T cell counts (245.7 cells/µL vs. 420.5 cells/µL, p < 0.05) and CD19+ B cell counts (97.3 cells/µL vs. 240.6 cells/µL, p < 0.05). Conclusion: The number of CMV infections was significantly higher in IIM patients, particularly in MDA5+ DM patients. Lower CD4+ T cells and CD19+ B cells were observed in CMV-IgM+ MDA5+ DM patients. CMV infection may have an important role in the pathogenesis and prognosis of MDA5+ DM by disrupting immunity.

Evaluation of Prognostic Factors in Anti-MDA5 Antibody-Positive Patients in Chongqing, China: A Retrospective Study.

OBJECTIVE: The aim of our study was to elucidate the potential prognostic factors in anti-melanoma differentiation-associated gene 5 (anti-MDA5)-positive patients. METHODS: We divided anti-MDA5-positive patients into death and survival groups. The differences in clinical characteristics were analyzed. RESULTS: A total of 56 cases were included. The death group comprised 10 (17.9%) cases, and the survival group comprised 46 (82.1%) cases. Median age of the death group was greater than the survival group, 59.50 years vs 39.25 years, p<0.05. The death group had lower lymphocyte count and albumin and higher erythrocyte sedimentation rate, ferritin and lactate dehydrogenase initially (p<0.05, respectively). Ground-glass opacity on chest computed tomography was found more often in the death group (p<0.05), in which there was an absence of honey-combed shadow initially. The diagnosis of interstitial pneumonia with autoimmune features was higher in the death group than the survival group (70% vs 13%, p<0.05). The median dose of maximum daily methylprednisolone in the death group (160 mg/d) was higher than that in the survival group (48 mg/d) (p<0.05). CONCLUSION: Advanced age, low lymphocyte count and albumin, and increased levels of inflammatory markers may portend poor prognosis in anti-MDA5-positive patients. Extra-large doses of glucocorticoid may have no additional benefit in these patients.

Adolescent-onset anti-MDA5 antibody-positive juvenile dermatomyositis with rapidly progressive interstitial lung disease and spontaneous pneumomediastinum: a case report and literature review.

BACKGROUND: Dermatomyositis with positive anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody has a distinct phenotype associated with small hand joint arthritis, mucocutaneous ulceration, palmar papules and less muscle involvement. It is also associated with increased risk of rapidly progressive interstitial lung disease (RP-ILD) and has a high mortality rate in adults. There is evidence that cases complicated with spontaneous pneumomediastinum (PNM) have an increase in mortality. While most of the evidence for this rare disease is derived from the adult literature, we report a case diagnosed in an adolescent complicated with both RP-ILD and PNM with a good outcome after aggressive immunosuppressive therapy. Our case also illustrates the potential challenges in diagnosis of this condition in the setting of non-specific clinical manifestations, the need for a high index of suspicion, and the importance of testing for myositis-specific antibodies (MSA) early to aid in diagnosis given the risk of rapid progression in these patients. CASE PRESENTATION: A 16-year-old Chinese female presented with fever and cough for 1 day, and finger swelling for 3 weeks. Physical examination revealed arthritis of fingers and wrists, ulcers and palmar papules over fingers, hyperpigmentation of interphalangeal joints, and rash over the neck. The diagnosis of dermatomyositis was made 1 month later with the onset of malar rash, Gottron's papules, calcinosis and myalgia. The diagnosis was supported by the presence of anti-MDA5 antibody and evidence of inflammatory myopathy on magnetic resonance imaging. In retrospect, she already had interstitial lung disease at first presentation manifested as cough and opacity on chest radiograph, which was later confirmed with chest computed tomography. She was treated according to adult guidelines with steroid and calcineurin inhibitor. Her disease was resistant to initial therapy and was complicated by RP-ILD and spontaneous PNM. Intensive immunosuppressive therapy including cyclophosphamide and rituximab were required to induce remission. CONCLUSIONS: Recognition of distinct clinical features of anti-MDA5 antibody-positive dermatomyositis and testing for MSA is crucial in patients with skin ulceration and abnormal pulmonary findings of unknown etiology, as prompt diagnosis with early aggressive treatment and anticipation of complications could make a difference in the outcome of this disease with high mortality.

ECG Changes Through Immunosuppressive Therapy Indicate Cardiac Abnormality in Anti-MDA5 Antibody-Positive Clinically Amyopathic Dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody, a dermatomyositis (DM)-specific antibody, is strongly associated with interstitial lung disease (ILD). Patients with idiopathic inflammatory myopathy (IIM) who are anti-MDA5 antibody positive [anti-MDA5 (+)] often experience chest symptoms during the active disease phase. These symptoms are primarily explained by respiratory failure; nevertheless, cardiac involvement can also be symptomatic. Thus, the aim of this study was to investigate cardiac involvement in anti-MDA5 (+) DM. A total of 63 patients with IIM who underwent electrocardiography (ECG) and ultrasound cardiography (UCG) during the active disease phase from 2016 to 2021 [anti-MDA5 (+) group, n = 21; anti-MDA5-negative (-) group, n = 42] were enrolled in the study, and their clinical charts were retrospectively reviewed. The ECG and UCG findings were compared between the anti-MDA5 (+) and anti-MDA5 (-) groups. All anti-MDA5 (+) patients had DM with ILD. The anti-MDA5 (+) group showed more frequent skin ulcerations and lower levels of leukocytes, muscle enzymes, and electrolytes (Na, K, Cl, and Ca) than the anti-MDA5 (-) group. According to the ECG findings obtained during the active disease phase, the T wave amplitudes were significantly lower for the anti-MDA5 (+) group than for the anti-MDA5 (-) group (I, II, and V4-6 lead; p < 0.01; aVF and V3, p < 0.05). However, the lower amplitudes were restored during the remission phase. Except for the E wave, A wave and Sep e', the UCG results showed no significant differences between the groups. Four patients with anti-MDA5 (+) DM had many leads with lower T wave and cardiac abnormalities (heart failure, diastolic dysfunction, myocarditis) on and after admission. Though anti-MDA5 (+) patients clinically improved after immunosuppressive therapy, some of their ECG findings did not fully recover in remission phase. In conclusion, anti-MDA5 (+) DM appears to show cardiac involvement (electrical activity and function) during the active phase. Further studies are necessary to clarify the actual cardiac condition and mechanism of these findings in patients with anti-MDA5 (+) DM.