The clinical relevance of WDFY4 in autoimmune diseases in diverse ancestral populations.

WD repeat- and FYVE domain-containing protein 4 (WDFY4), coded by a gene on 10q11.23, is a member of the BEACH (Beige and Chediak-Higashi) domain-containing family. Genome-wide association studies identified WDFY4 variants as a risk factor for SLE in Asian and European populations. WDFY4 variants are also associated with RA and primary biliary cholangitis, in different ancestry populations. The WDFY4 protein plays an essential role in the cross-presentation of classic dendritic cells, reactive oxygen species-induced apoptosis of CD8+ T cells, and non-canonical autophagic activity in B cells. A novel variant rs7919656 was identified in Japanese clinically amyopathic dermatomyositis patients, with a highly expressed truncated isoform augmenting the melanoma differentiation-associated gene 5 (MDA5) signalling pathway. The same variant was later found to be significantly associated with RP-ILD in Chinese MDA5+DM patients. Here, we briefly review the association of WDFY4 with autoimmune diseases and its known function in immune response.

Proteomic profiling identifies SPP1 associated with rapidly progressive interstitial lung disease in anti-MDA5-positive dermatomyositis.

BACKGROUND: Anti-melanoma differentiation-associated gene five antibody positive (MDA5+) dermatomyositis (DM) is significantly associated with rapidly progressive interstitial lung disease (RP-ILD). Early detection of RP-ILD remains a major challenge. This study aims to identify and validate prognostic factors for RP-ILD in MDA5+ DM patients. METHODS: Plasma samples from 20 MDA5+ DM patients and 10 healthy controls (HC) were collected for proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The proteins of interest were validated in independent samples (20 HC, 20 MDA5+ DM with RP-ILD, and 20 non-RP-ILD patients) with enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 413 differentially expressed proteins (DEPs) were detected between the MDA5+ DM patients and HC. When comparing DEPs between RP-ILD and non-RP-ILD patients, 79 proteins were changed in RP-ILD patients, implicating acute inflammatory response, coagulation, and complement cascades. Six candidate biomarkers were confirmed with ELISA. Secreted phosphoprotein 1 (SPP1), serum amyloid A1 (SAA1), and Kininogen 1 (KNG1) concentrations were significantly elevated in RP-ILD patients than those in non-RP-ILD patients and HC. In the different clinical subgroups, SPP1 was particularly elevated in the high-risk RP-ILD subgroup of MDA5+ DM. CONCLUSION: This study provides novel insights into the pathogenesis of RP-ILD development in MDA5+ DM and suggests the plasma protein SPP1 could serve as a potential blood biomarker for RP-ILD early warning.

A nomogram based on clinical factors and CT radiomics for predicting anti-MDA5+ DM complicated by RP-ILD.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) DM complicated by rapidly progressive interstitial lung disease (RP-ILD) has a high incidence and poor prognosis. The objective of this study was to establish a model for the prediction and early diagnosis of anti-MDA5+ DM-associated RP-ILD based on clinical manifestations and imaging features. METHODS: A total of 103 patients with anti-MDA5+ DM were included. The patients were randomly split into training and testing sets of 72 and 31 patients, respectively. After image analysis, we collected clinical, imaging and radiomics features from each patient. Feature selection was performed first with the minimum redundancy and maximum relevance algorithm and then with the best subset selection method. The final remaining features comprised the radscore. A clinical model and imaging model were then constructed with the selected independent risk factors for the prediction of non-RP-ILD and RP-ILD. We also combined these models in different ways and compared their predictive abilities. A nomogram was also established. The predictive performances of the models were assessed based on receiver operating characteristics curves, calibration curves, discriminability and clinical utility. RESULTS: The analyses showed that two clinical factors, dyspnoea (P = 0.000) and duration of illness in months (P = 0.001), and three radiomics features (P = 0.001, 0.044 and 0.008, separately) were independent predictors of non-RP-ILD and RP-ILD. However, no imaging features were significantly different between the two groups. The radiomics model built with the three radiomics features performed worse than the clinical model and showed areas under the curve (AUCs) of 0.805 and 0.754 in the training and test sets, respectively. The clinical model demonstrated a good predictive ability for RP-ILD in MDA5+ DM patients, with an AUC, sensitivity, specificity and accuracy of 0.954, 0.931, 0.837 and 0.847 in the training set and 0.890, 0.875, 0.800 and 0.774 in the testing set, respectively. The combination model built with clinical and radiomics features performed slightly better than the clinical model, with an AUC, sensitivity, specificity and accuracy of 0.994, 0.966, 0.977 and 0.931 in the training set and 0.890, 0.812, 1.000 and 0.839 in the testing set, respectively. The calibration curve and decision curve analyses showed satisfactory consistency and clinical utility of the nomogram. CONCLUSION: Our results suggest that the combination model built with clinical and radiomics features could reliably predict the occurrence of RP-ILD in MDA5+ DM patients.

Metagenome-wide association study of gut microbiome features for myositis.

PURPOSE: The clinical relevance and pathogenic role of gut microbiome in both myositis and its associated interstitial lung disease (ILD) are still unclear. The purpose of this study was to investigate the role of gut microbiome in myositis through comprehensive metagenomic-wide association studies (MWAS). METHODS: We conducted MWAS of the myositis gut microbiome in a Chinese cohort by using whole-genome shotgun sequencing of high depth, including 30 myositis patients and 31 healthy controls (HC). Among the myositis patients, 11 developed rapidly progressive interstitial lung disease (RP-ILD) and 10 had chronic ILD (C-ILD). RESULTS: Analysis for overall distribution level of the bacteria showed Alistipes onderdonkii, Parabacteroides distasonis and Escherichia coli were upregulated, Lachnospiraceae bacterium GAM79, Roseburia intestinalis, and Akkermansia muciniphila were downregulated in patients with myositis compared to HC. Bacteroides thetaiotaomicron, Parabacteroides distasonis and Escherichia coli were upregulated, Bacteroides A1C1 and Bacteroides xylanisolvens were downregulated in RP-ILD cases compared with C-ILD cases. A variety of biological pathways related to metabolism were enriched in the myositis and HC, RP-ILD and C-ILD comparison. And in the analyses for microbial contribution in metagenomic biological pathways, we have found that E. coli played an important role in the pathway expression in both myositis group and myositis-associated RP-ILD group. Anti-PL-12 antibody, anti-Ro-52 antibody, and anti-EJ antibody were found to have positive correlation with bacterial diversity (Shannon-wiener diversity index and Chao1, richness estimator) between myositis group and control groups. The combination of E. coli and R. intestinalis could distinguish myositis group from HC effectively. R. intestinalis can also be applied in the distinguishment of RP-ILD group vs. C-ILD group in myositis patients. CONCLUSION: Our MWAS study first revealed the link between gut microbiome and pathgenesis of myositis, which may help us understand the role of gut microbiome in the etiology of myositis and myositis-associated RP-ILD.

"Management of myositis associated interstitial lung disease".

Idiopathic inflammatory myopathies (IIM) are rare disorders characterised by the presence of skeletal muscle inflammation, with interstitial lung disease (ILD) being the most frequent pulmonary manifestation. The spectrum of clinical presentations of myositis related ILD (M-ILD) encompasses a chronic process to a rapidly progressive ILD (RP-ILD); which is associated with a high mortality rate. The most effective treatments remain controversial and poses a unique challenge to both rheumatologists and respiratory physicians to manage. Given the rare heterogenous nature of M-ILD, there is a paucity of data to guide treatment. The cornerstone of existing treatments encompasses combinations of immunosuppressive therapies, as well as non-pharmacological therapies. In this review, we aim to summarize the current pharmacological therapies (including its dosing regimens and side effects profiles) and non-pharmacological therapies. Based on the existing literature to date, we propose a treatment algorithm for both chronic M-ILD and RP-ILD.

Coexistence of Anti-Ro52 Antibodies in Anti-MDA5 Antibody-Positive Dermatomyositis Is Highly Associated With Rapidly Progressive Interstitial Lung Disease and Mortality Risk.

OBJECTIVE: Interstitial lung disease (ILD) is a common extramuscular complication contributing to significant morbidity and mortality in patients with dermatomyositis (DM) who are positive for antimelanoma differentiation-associated gene 5 antibody (anti-MDA5+). We conducted this study to investigate the association of anti-Ro52 antibodies with clinical characteristics and prognosis in patients with anti-MDA5+ DM. METHODS: We assessed a cohort of 246 patients with anti-MDA5+ DM. To calculate hazard ratios and 95% CIs for rapidly progressive ILD (RP-ILD) and death while controlling for potential confounders, variables selected by univariate Cox regression analysis were included in a multivariate Cox regression model with the stepwise forward-selection method. A 2-tailed analysis with P < 0.05 was considered to be statistically significant. RESULTS: A total of 246 patients with anti-MDA5+ DM were enrolled; 70 patients were male, and the patient group had an average age of 53.1 (12.4) years. Anti-Ro52 was present in 64.2% (158/246) patients. Patients with anti-MDA5+ DM who were positive for anti-Ro52 had a higher rate of RP-ILD (log-rank P < 0.001) and a higher mortality rate (log-rank P = 0.01). For patients with anti-MDA5+ DM who were positive for anti-Ro52, those with a short disease course and high inflammation were at increased risk of RP-ILD and death. The appearance of active rash was an independent protective factor of death. CONCLUSION: Anti-Ro52 antibodies were highly prevalent in patients with anti-MDA5+ DM, and their coexistence correlated with a higher rate of RP-ILD and mortality. Patients with a short disease course, with increased inflammation, and without rash were more likely to have a poor prognosis.

Seasonal Effect on Disease Onset and Presentation in Anti-MDA5 Positive Dermatomyositis.

OBJECTIVE: To investigate the seasonal variation of disease onset and presentation in an ethno-geographically homogeneous cohort of patients with anti-MDA5 positive dermatomyositis (DM). METHODS: This was a multi-centered, retrospective cohort study. Adult Chinese anti-MDA5 positive DM patients were identified from the Hong Kong Myositis Registry and the Clinical Data Analysis and Reporting System from 2015 to 2020. Equal number of IIM patients without anti-MDA5 antibody were selected as controls. Line blot immunoassay was used to detect the autoantibodies. The onset of disease, presenting clinical features and subsequent complications were analyzed for any seasonality. RESULTS: A total of 110 patients with anti-MDA5 positive DM were studied. The mean age at diagnosis was 53.0 ± 12.3 years and the mean follow-up duration was 20.6 ± 23.1 months. Two third of the patients (66%) had the clinically amyopathic phenotype. Most patients (86%) had interstitial lung disease (ILD) and 42% developed rapidly progressive ILD (RP-ILD). The mortality was 40% and the commonest cause was RP-ILD. Chi-square test showed significantly less patients had symptom onset in July to September. However, no particular seasonal pattern was observed in the anti-MDA5 negative IIM controls. RP-ILD occurred more frequently in patients with disease onset in October to December. Anti-MDA5 positive DM patients with disease onset in warmer months (April to September) were more likely to have clinical muscle involvement. CONCLUSION: Apparent seasonal patterns were noted in our ethno-geographically identical anti-MDA5 positive DM patients, but not in IIM patients in general. Certain environmental factors, particularly infection, might be implicated.

Combination Therapy with Rituximab, Tofacitinib and Pirfenidone in a Patient with Rapid Progressive Interstitial Lung Disease (RP-ILD) Due to MDA5 Antibody-Associated Dermatomyositis: A Case Report.

Anti-melanoma differentiation-associated protein 5 (MDA5)-positive rapidly progressive interstitial lung disease (RP-ILD) is associated with poor prognosis, and the most effective therapeutic intervention has not been established. Herein we report a case of a 45-year-old female patient who presented with myalgia, Gottron's papules with ulceration, and dyspnea on exertion which became aggravated within weeks. Laboratory examination and electromyography confirmed myopathy changes, and a survey of myositis-specific antibodies was strongly positive for anti-MDA5 antibody. High-resolution chest tomography suggested organizing pneumonia with rapidly progressive changes within the first month after diagnosis of the disease. Anti-MDA5-associated dermatomyositis with RP-ILD was diagnosed. Following combination therapy with rituximab, tofacitinib and pirfenidone, clinical symptoms, including cutaneous manifestation, respiratory conditions and radiographic changes, showed significant and sustainable improvement. To our knowledge, this is the first reported case of anti-MDA5-associated dermatomyositis with RP-ILD successfully treated with the combination of rituximab, tofacitinib, and pirfenidone.

Slowly progressive interstitial lung disease preceding typical dermatomyositis symptoms in anti-melanoma differentiation-associated gene 5 antibody-positive clinically amyopathic dermatomyositis.

A 73-year-old woman who visited our hospital complaining of dry cough for three months was refractory to antimicrobial therapy. Chest computed tomography revealed subpleural consolidation. Specimens obtained from surgical lung biopsy revealed subpleural perilobular airspace organization and fibrosis. After the biopsy, mechanic's hand and Gottron's papules appeared, and anti-melanoma differentiation-associated gene 5 (MDA5) antibody was found to be positive. Subsequently, anti-MDA5 antibody measured in cryopreserved serum from her first admission proved to be positive. It is difficult to suspect the presence of anti-MDA-5 antibody in patients with interstitial lung disease without typical dermatomyositis symptoms or slow disease progression.

Early initiation of plasma exchange therapy for a patient with anti-MDA5 autoantibody-positive dermatomyositis developing rapidly progressive interstitial lung disease.

Dermatomyositis (DM) is a categorised as one of idiopathic inflammatory myopathy (IIM) indicated by symmetrical proximal muscle weakness as well as characteristic cutaneous manifestations typical of DM. Clinically amyopathic dermatomyositis (CADM), a subtype of DM, shows only the skin involvement without any clinical signs of myositis. This condition is often associated with fatal anti-MDA5 antibody-positive rapidly progressive interstitial lung disease (RP-ILD), especially in Eastern Asian populations. Here, we report a CADM patient with anti-MDA5 antibody-positive RP-ILD whom we successfully treated by early initiation of plasma exchange (PE) together with multiple immunosuppressive therapies. In this patient, initial treatment with high-dose prednisolone (PSL), tacrolimus and intermittent intravenous cyclophosphamide had resulted in no obvious improvement in the respiratory condition. Therefore, soon after the first evaluation, we initiated PE therapy in addition to these multiple immunosuppressive therapies. Although the patient had pneumomediastinum, cytomegalovirus and fungal infections over the clinical course, RP-ILD did gradually improved and the anti-MDA5 titre decreased down to within the normal range paralleled by improvement in the patient's respiratory condition.

Prognostic values of anti-Ro52 antibodies in anti-MDA5-positive clinically amyopathic dermatomyositis associated with interstitial lung disease.

OBJECTIVE: Anti-Ro52 antibody often co-occurs with anti-Jo1 antibody in antisynthetase syndrome and their co-occurrence correlates with a more aggressive clinical phenotype and poorer prognosis. The strong association of anti-Ro52 antibody with anti-melanoma differentiation-associated protein-5 (anti-MDA5) antibody has been indicated in juvenile myositis. The aim of this study was to assess the clinical significance of anti-Ro52 antibody in a cohort of adult patients with anti-MDA5-positive clinically amyopathic dermatomyositis with interstitial lung disease (CADM-ILD). METHODS: We assessed a cohort of 83 consecutive patients with anti-MDA5-positive CADM-ILD. Anti-MDA5 antibodies and anti-Ro52 antibodies were detected in immunoblotting and semi-quantitatively analysed by densitometry. Clinical features and the 24 month survival were compared between anti-MDA5-positive patients with and without anti-Ro52 antibodies. RESULTS: Anti-Ro52 antibodies were found in 74.7% of anti-MDA5-positive CADM-ILD patients and were associated with an increased frequency of rapidly progressive interstitial lung disease (RP-ILD; 54.8% vs 23.8%; P = 0.014) and cutaneous ulcerations (27.4% vs 4.8%; P = 0.033). The cumulative 24 month survival rate tended to be lower in patients with anti-Ro52 antibodies than patients without (59.9% vs 85.7%; P = 0.051). The combination of anti-Ro52 antibody status and anti-MDA5 antibody levels further stratified patients' survival rates, showing that the survival rate of patients who were dual positive for anti-MDA5 antibody and anti-Ro52 antibody was significantly lower than patients with mild positive anti-MDA5 antibody alone (59.9% vs 100%; P = 0.019). CONCLUSION: Anti-Ro52 antibody is highly prevalent in anti-MDA5-positive CADM-ILD patients and their coexistence correlates with a subgroup of patients with more aggressive phenotypes. The combination of anti-MDA5 antibody levels and anti-Ro52 antibody status could help to predict patients' prognosis and guide risk-based therapy.

Acute lung injury after plasma exchange in a patient with anti-MDA5 antibody-positive, rapidly progressive, interstitial lung disease：A case report.

The presence of anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is closely associated with rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis. Despite intensive immunosuppressive therapies, some of these patients still have a poor prognosis with few treatment options. Although removal of pathogenic autoantibodies and cytokines by plasma exchange (PE) could be a treatment option, its safety and efficacy have never been determined. We report a patient with anti-MDA5 Ab-positive RP-ILD who was refractory to intensive therapies including steroids, cyclosporine, and intravenous cyclophosphamide, and then treated by PE to prevent the progression of RP-ILD. Shortly after the initiation of PE therapy, however, his respiratory condition suddenly deteriorated due to acute pulmonary edema and the patient died on the following day. Transfusion-related acute lung injury (TRALI) would be the most likely cause of the acute pulmonary edema because there was no sign of circulatory overload. To the best of our knowledge, this is the first report showing a critical adverse event associated with PE therapy for these patients. This case supports the idea that the presence of ILD could increase a risk for TRALI and therefore we should carefully evaluate the eligibility for PE therapy of anti-MDA5 Ab-positive RP-ILD patients given the risk of acute lung injury. Further studies collecting more clinical data are necessary to assess the efficacy, safety, and risk factors of PE therapy for these patients.

Clinical characteristics of dermatomyositis patients with isolated anti-Ro-52 antibody associated rapid progressive interstitial lung disease: Data from the largest single Chinese center.

AIM: To describe and expand the phenotype of isolated anti-Ro-52-associated rapid progressive interstitial lung disease (RP-ILD) in Dermatomyositis(DM) in Chinese patients. METHODS: 491 patients with PM/DM-ILD hospitalized in the China-Japan Friendship Hospital from 2000 to 2017 were screened retrospectively. All proven cases of isolated anti-Ro-52-associated RP-ILD were selected for inclusion. The clinical features in this group were recorded. RESULTS: Isolated Ro-52 antibodies existed in 20 PM/DM-ILD patients. Among them 5 patients developed RP-ILD. The 5 patients had typical rashes including Gottron's sign (80%), Helitrope rash (80%) and mechanic's hands (100%), but only few patients (20%) had arthralgia and muscle weakness. All patients had elevated levels of serum ferritin and decreased counts of CD3+ T cells. The estimated high-resolution computed tomography (HRCT) patterns of the five patients showed organizing pneumonia (OP) while RP-ILD patients without Ro-52 antibodies and non-RP-ILD patients with isolated Ro-52 antibodies mainly showed non-specific interstitial pneumonia (NSIP) patterns(P < 0.05). Although one patient died of infection after one month, 80%(4/5) of patients had good response to glucocorticoid treatment and these four patients survived were all alive at the end of follow-up. The survival rate in this group was the highest than those in RP-ILD patients with other myositis specific autoantibodies though the difference had no statistically significance. CONCLUSIONS: A small group of patients with isolated anti-Ro-52 antibody in DM could develop RP-ILD, which mainly presented OP on HRCT. Patients with isolated anti-Ro-52 antibody associated RP-ILD responded well to therapy and had good prognosis in DM.

Anti-MDA5 antibody-positive rapidly progressive interstitial pneumonia without cutaneous manifestations.

A 47-year-old man was referred to our hospital with a 1-month history of fever and dyspnea after inhalation of insecticide in a confined space. We diagnosed rapidly progressive interstitial pneumonia. High-dose methylprednisolone, tacrolimus, and intermittent infusion of cyclophosphamide were administered. His condition rapidly deteriorated; therefore, extracorporeal membrane oxygenation therapy was performed. Unfortunately, he died 69 days after admission. Although typical skin findings suggestive of dermatomyositis were absent, anti-melanoma differentiation-associate gene (anti-MDA5) antibody was positive. Our findings suggest that in patients with hyperferritinemia and rapidly progressive interstitial lung disease (RP-ILD) demonstrating random ground glass shadows and peripheral consolidations by high-resolution computed tomography (HRCT) even if skin manifestations related to dermatomyositis are not complicated, we should assume anti-MDA5 antibody-positive interstitial pneumonia.

Correlation between disease activity and serum ferritin in clinically amyopathic dermatomyositis with rapidly-progressive interstitial lung disease: a case report.

BACKGROUND: Clinically amyopathic dermatomyositis with anti-Melanoma Differentiation-Associated gene 5 (MDA5) antibody often presents with severe interstitial lung disease. Although serum ferritin level is known to reflect interstitial lung disease activity, there are few case reports describing this association. CASE PRESENTATION: A 58-year-old man was referred to our outpatient clinic with a 3-week history of cough and respiratory distress. He had erythema over the V area of the neck and a Gottron's sign. Chest computed tomography revealed diffuse ground-glass opacities and reticular shadows in both lungs. Test for anti-MDA5 antibody was positive. After admission, he received triple combination therapy (methylprednisolone pulse therapy, tacrolimus, and cyclophosphamide). However, his respiratory condition worsened as the serum ferritin level increased. Despite no apparent deterioration on chest radiography, he ultimately died due to respiratory failure. CONCLUSIONS: In this case, triple combination therapy was not effective for the patient's respiratory condition. The serum ferritin level was correlated with disease activity and was more useful than chest radiography for monitoring clinical status.

Lung histopathological pattern in a survivor with rapidly progressive interstitial lung disease and anti-melanoma differentiation-associated gene 5 antibody-positive clinically amyopathic dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies are specific indicators of patients with dermatomyositis, particularly clinically amyopathic dermatomyositis (CADM). CADM is occasionally accompanied by fatal, treatment-resistant, rapidly-progressive interstitial lung disease (RP-ILD). All previous reports showed that histopathological findings in RP-ILD with anti-MDA5 antibody-positive CADM indicated diffuse alveolar damage (DAD). This is the first report describing a non-DAD pattern in RP-ILD with anti-MDA5 antibody-positive CADM, which was improved by immunosuppressive therapy. This case may be a milder clinical phenotype than a typical DAD pattern in RP-ILD with anti-MDA5 antibody-positive CADM.