Anti-MDA5 Positive Dermatomyositis Research Articles

OA16 Clinical and biochemical improvement following daratumumab therapy for anti-MDA5 antibody positive dermatomyositis with rapidly progressive interstitial lung disease: a case report

Abstract Background/Aims Anti-melanoma differentiation-associated 5 gene autoantibody (anti-MDA5) positive dermatomyositis (DM) with rapidly progressive interstitial lung disease (RP-ILD) represents the most severe and difficult-to-treat form of autoimmune myositis with unfavourable 6-month survival rates despite intensive treatment strategies of combination therapy with glucocorticoids, cyclophosphamide, calcineurin inhibitors, mycophenolate mofetil and rituximab. We describe a case of anti-MDA5 positive DM with RP-ILD that was refractory to intensive combination therapy, requiring courses of rescue plasmapheresis, before eventually responding to intravenous daratumumab. Methods A 30-year-old non-smoking Chinese man who was previously well was hospitalised after 3 weeks of intermittent pyrexia, non-productive cough, lethargy, rashes and myalgia. Examination revealed typical cutaneous changes of dermatomyositis, bilateral mid-to-lower zone inspiratory crepitations in his chest with no proximal muscle weakness or synovitis. Initial investigations demonstrated elevations in creatine kinase, C-reactive protein, erythrocyte sedimentation rate, lactate dehydrogenase, ferritin and neutrophil-to-lymphocyte ratio. Although an initial chest radiograph was normal, CT thorax 4 days later showed non-specific ground-glass opacities with consolidation in both lower lobes. Anti-MDA5 antibodies were strongly positive on EUROLINE Inflammatory Myopathies 16 Ag (IgG) commercial line immunoblot. He was transferred to our centre for further care one week after hospitalisation and was intubated on arrival for type I respiratory failure. He was initiated on combination therapy of intravenous methylprednisolone, intravenous rituximab, hydroxychloroquine, tofacitinib and was also treated with plasmapheresis to remove pathogenic anti-MDA5 antibodies. Although his condition improved initially with successful extubation within one week, the disease remained active in the following months with several admissions for infection-related issues and progression of RP-ILD. Despite various combinations of immunosuppressives and further courses of plasmapheresis, at 6 months post-diagnosis he continued to require a minimum daily prednisolone dose of 45mg (0.625mg/kg/day), remaining positive for anti-MDA5 antibodies on the immunoblot assay, with persistently elevated serum ferritin and transaminases. As such, he was treated with four doses of intravenous daratumumab in an attempt to deplete the long-lasting plasma cells that may be driving the disease. Results Following daratumumab treatment, the anti-MDA5 antibody turned negative on the immunoblot assay with normalisation of ferritin and transaminases, with corresponding improvement in lung function tests and chest radiograph findings. 3 months post-daratumumab, he remains clinically well on hydroxychloroquine, tofacitinib and nintedanib, with successful continuing taper of prednisolone. Conclusion Daratumumab is an anti-CD38 monoclonal antibody licensed for the treatment of multiple myeloma which has been used off-label for other refractory autoimmune conditions such as SLE. It is postulated that besides CD19/20 positive B cells, CD38 positive long-lived autoantibody-secreting plasma cells are essential drivers of chronic inflammation in these autoimmune diseases. In our patient with anti-MDA5 DM and RP-ILD, the use of daratumumab was well-tolerated and led to definite clinical and biochemical improvement. Disclosure L. Koh: None. G. Chai: None. M. Manghani: None. X. Lim: None. B.P.L. Leung: None. C. Chua: None.

Rapidly progressive interstitial lung disease risk prediction in anti-MDA5 positive dermatomyositis: the CROSS model.

The prognosis of anti-melanoma differentiation-associated gene 5 positive dermatomyositis (anti-MDA5+DM) is poor and heterogeneous. Rapidly progressive interstitial lung disease (RP-ILD) is these patients' leading cause of death. We sought to develop prediction models for RP-ILD risk in anti-MDA5+DM patients. Patients with anti-MDA5+DM were enrolled in two cohorts: 170 patients from the southern region of Jiangsu province (discovery cohort) and 85 patients from the northern region of Jiangsu province (validation cohort). Cox proportional hazards models were used to identify risk factors of RP-ILD. RP-ILD risk prediction models were developed and validated by testing every independent prognostic risk factor derived from the Cox model. There are no significant differences in baseline clinical parameters and prognosis between discovery and validation cohorts. Among all 255 anti-MDA5+DM patients, with a median follow-up of 12 months, the incidence of RP-ILD was 36.86%. Using the discovery cohort, four variables were included in the final risk prediction model for RP-ILD: C-reactive protein (CRP) levels, anti-Ro52 antibody positivity, short disease duration, and male sex. A point scoring system was used to classify anti-MDA5+DM patients into moderate, high, and very high risk of RP-ILD. After one-year follow-up, the incidence of RP-ILD in the very high risk group was 71.3% and 85.71%, significantly higher than those in the high-risk group (35.19%, 41.69%) and moderate-risk group (9.54%, 6.67%) in both cohorts. The CROSS model is an easy-to-use prediction classification system for RP-ILD risk in anti-MDA5+DM patients. It has great application prospect in disease management.

Hypouricemia as a novel predictor of mortality in anti-MDA5 positive dermatomyositis patients with ILD: A retrospective cohort study

ObjectiveAnti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+ DM) is a unique subtype of idiopathic inflammatory myopathy (IIM) that is associated with rapidly progressive interstitial lung disease (RPILD) and high mortality. This retrospective study aimed to identify predictors of mortality and discover novel easily detectable indicators. MethodsWe retrospectively reviewed 183 MDA5+ DM-ILD patients who were from West China Hospital of Sichuan University myositis cohort, the largest single-center cohort of southwest China, from January 2016 to October 2021. Clinical characteristics were reviewed, and risk factors for mortality were determined by univariate and multivariable Cox regression analyses. ResultsOf the 183 MDA5+ DM-ILD patients, 59 were presented with RP-ILD, and 53 died during the follow-up period. Compared with the survived patients, deceased patients had higher rates of dyspnea, higher concentrations of CRP, and LDH, but lower rates of heliotrope sign, lower quantity of lymphocyte and lower levels of serum uric acid (SUA). Notably, patients with hypouricemia (SUA <154 μmol/L) had higher concentrations of CRP and LDH, higher neutrophil counts, lower lymphocyte counts and higher mortality rate when compared with the non-hypouricemia group. Multivariate Cox regression analyses confirmed that hypouricemia, smoking, RPILD, high HRCT score, elevated LDH, and lymphopenia were independent risk factors for mortality in MDA5+ DM-ILD patients. Moreover, patients with hypouricemia had significantly lower survival rates than non-hypouricemia patients. ConclusionOur study identified hypouricemia as a non-redundant promising prognostic factor for the mortality of MDA5+ DM-ILD patients, which may hopefully provide insight into the prevention and pathogenesis study.

Ground-glass opacity score predicts the prognosis of anti-MDA5 positive dermatomyositis: a single-centre cohort study

ObjectiveDermatomyositis (DM) positive with anti-melanoma differentiation-associated gene 5 (anti-MDA5-DM) is a systemic autoimmune disease with high mortality. This study aimed to explore the risk factors of death in anti-MDA5-DM and validate a prediction model for all-cause mortality in anti-MDA5-DM.MethodWe conducted a retrospective study using a single-centre cohort of patients with newly onset anti-MDA5-DM from June 1, 2018 to August 31, 2021. Patients were divided into four groups according to baseline ground-glass opacity (GGO) score: Group A, GGO ≤ 1; Group B, 1 < GGO ≤ 2; Group C, 2 < GGO ≤ 3; Group D, GGO > 3. The primary outcome was death during the follow-up. Secondary outcomes included death within 3, 6, 12 months, severe infection, and remission during the first 12 months.ResultsA total of 200 patients were included in the study. Based on multivariable Cox regression, the prognostic factors at baseline were identified as CRP > 5 mg/L, serum ferritin (SF) > 600ng/ml, positive anti-Ro52 antibody, prophylactic use of compound sulfamethoxazole (SMZ Co), four-category GGO score: GGO ≤ 1, 1 < GGO ≤ 2, 2 < GGO ≤ 3, GGO > 3. The final mortality of four groups was 16.4, 22.2, 48.5, 92.0%, respectively. Compared with Group A, the Hazards Ratio (HR) of Group B was 1.408, (p = 0.408), HR of Group C was 3.433 (p = 0.005), HR of Group D was 4.376 (p = 0.001).ConclusionsGGO score is a reliable predictor for risk stratification in anti-MDA5-DM and may provide guidance for individualized managements of patients.

IFN-beta and EIF2AK2 are potential biomarkers for interstitial lung disease in anti-MDA5 positive dermatomyositis.

Dermatomyositis (DM) with positive anti-melanoma differentiation-related gene 5 (MDA5) antibody is an autoimmune disease with multiple complications. Interstitial lung diseases (ILD) are significantly associated with DM and are particularly related to MDA5+ DM. This article aimed to explore potential molecular mechanisms and develop new diagnostic biomarkers for MDA5+ DM-ILD. The series matrix files of DM and NSIP were downloaded from the Gene Expression Omnibus (GEO) database to identify the differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) was used to screen the common enriched pathways related to DM and NSIP. Next, the co-expressed differential expressed genes (co-DEGs) between MDA5+, MDA5- and NSIP groups were identified by Venn plots, and then selected for different enrichment analyses and protein-protein interaction (PPI) network construction. The mRNA expression levels of IFN-beta and EIF2AK2 were measured by RT-qPCR. The protein expression levels of IFN-beta were measured by ELISA. Using GSEA, the enriched pathway "herpes simplex virus 1 infection" was both up-regulated in DM and NSIP. Enrichment analysis in MDA5+ DM, MDA5- DM and NSIP reported that the IFN-beta signalling pathway was an important influencing factor in the MDA5+ DM-ILD. We also identified that eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) was an important gene signature in the MDA5+ DM-ILD by PPI analysis. The expression levels of IFN-beta and EIF2AK2 were significantly increased in MDA5+ DM-ILD patients. IFN-beta and EIF2AK2 contributed to the pathogenesis of MDA5+ DM-ILD, which could be used as potential therapeutic targets.

α2,3-Sialylation with Fucosylation Associated with More Severe Anti-MDA5 Positive Dermatomyositis Induced by Rapidly Progressive Interstitial Lung Disease.

The online version contains supplementary material available at 10.1007/s43657-023-00096-z.

A Preliminary Study of Frequency and Clinical Relevance of Cytotoxic Peripheral CD4 and CD8 T Cells in Patients with Anti-MDA5 Positive Dermatomyositis.

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+DM) is an autoimmune disease frequently accompanied by rapidly progressive interstitial lung disease (RP-ILD) with high mortality. T cells are implicated in the pathogenesis of MDA5+DM and this study aims to measure the frequency and clinical relevance of cytotoxic CD4 and CD8 T cells in this disease. T cells expressing Perforin, Granzyme B (GZMB) and Granzyme K (GZMK) were analyzed by flow cytometry from peripheral blood of 19 patients with active MDA5+DM and 19 age- and sex-matched healthy donors (HDs). The frequency of CD4 and CD8 T cells and the cytotoxic subsets were compared between patients with MDA5+DM and HDs. Correlations within T cell subsets and between T cell subsets and clinical parameters of lactate dehydrogenase (LDH), ferritin, neutrophil-to-lymphocyte ratio (NLR), and Myositis Intention-to-Treat Index (MITAX) were evaluated. Compared with HDs, patients with active MDA5+DM significantly had increased frequency of CD4 T cells, and reduced frequency of GZMK+GZMB- CD8 T cells. Furthermore, the frequency of GZMK+GZMB- CD8 T cells positively correlated with serum ferritin levels in active MDA5+DM patients. Notably, the patients in the Dead group of MDA5+DM had a significant higher frequency of GZMK+GZMB- CD4 and CD8 T cells. Substantial changes of cytotoxic T cell subsets are observed in active MDA5+DM patients. In addition, a high frequency of GZMK+GZMB- CD4 and CD8 T cells is associated with unfavorable prognosis in MDA5+DM. More studies are warranted to further explore the roles of cytotoxic T cells in MDA5+DM.

Neutrophil-to-lymphocyte ratio is a predictive marker for anti-MDA5 positive dermatomyositis

BackgroundNLR is a systemic inflammatory marker that have been associated with overall survival in patients with some rapidly progressive disease. There are few data about the diagnostic and predictive value of NLR in autoimmune diseases, and it has not been described in anti-MDA5 positive DM. We try to correlate neutrophil-to-lymphocyte ratio (NLR) with fatality from dermatomyositis in anti-MDA5 positive patients.MethodA retrospective study in which 195 patients were enrolled was conducted. Clinical and laboratory information was collated and ratios of neutrophil to lymphocyte counts (NLR) calculated. The primary end point was all-cause death.ResultOf the 195 patients studied, all had interstitial lung disease, including 140 survivors and 55 non-survivors. An optimal NLR cut-off value of 4.86 for mortality prediction was identified. The NLR of non-survivors was significantly higher than that of survivors (p < 0.001). Plasma levels of lactate dehydrogenase (LDH) and C-reactive protein were significantly increased when NLR was greater than 4.86. Results of multivariate analysis established that NLR > 4.86 was an independent predictor of mortality (HR: 2.52; 95%CI: 1.33–4.78; p = 0.005). Abstinence from smoking (HR: 2.66; 95%CI: 1.33–4.78; p = 0.003), emergence of rapidly progressive interstitial lung disease (RPILD; HR: 4.38; 95%CI: 2.37–8.08; p < 0.001), low plasma LDH (HR: 3.82; 95%CI: 2.06–7.11; p < 0.001) and presentation with dyspnea (HR: 2.17; 95%CI: 1.22–3.86; p = 0.009) were all protective factors predictive of survival.ConclusionNLR is a cost-effective and widely accessible biomarker with utility for risk stratification in patients with anti-MDA5 + dermatomyositis.

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.

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

ObjectiveTo investigate the seasonal variation of disease onset and presentation in an ethno-geographically homogeneous cohort of patients with anti-MDA5 positive dermatomyositis (DM).MethodsThis 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.ResultsA 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.ConclusionApparent 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.

Spontaneous Intramuscular Hemorrhage in Anti-MDA5 Positive Dermatomyositis: A Case Series and Literature Review.

ObjectiveSpontaneous intramuscular hemorrhage (SIH) is a rare but life-threatening complication associated with dermatomyositis (DM). This study reported a case series of SIH associated with DM. In addition, the characteristics and prognostic effects for this complication were analyzed based on literature review.MethodsWe reported seven cases of anti-melanoma differentiation-associated gene five positive dermatomyositis (MDA5+DM) complicated by SIH in our single-center cohort, and a comprehensive literature review was performed. Clinical characteristics, treatment, and outcome data of all eligible reported cases were summarized. Potential prognostic effects were identified by comparisons between the deceased and survivors.ResultsAmong cumulatively reported patients with DM patients and SIH, the overall mortality was 60.9% (14/23) (including our cases). Fourteen out of nineteen (73.7%) hemorrhagic events occurred within 6 months of disease onset. Anti-MDA5 antibody predominated in those myositis-specific antibodies available cases (8/10), although patients with positive anti-NXP2 and anti-Mi2 have also been documented. Iliopsoas (52.2%, 12/23) was the most frequently involved bleeding location. Bleeding in deep muscles was identified to be associated with poorer prognosis. The mortality of patients with DM and deep muscular hematoma (non-palpable) (80%, 12/15) was significantly higher than that of patients with only superficial muscular hematoma (palpable) (25%, 2/8) (p =0.023).ConclusionSpontaneous hematoma in non-palpable deep muscles probably leads to excess mortality in dermatomyositis, particularly for those with anti-MDA5 antibody, which often occurs within 6 months of disease onset. Clinicians should be vigilant to this rare but potentially fatal complication and carefully balance the risks and benefits of prophylactic anti-thrombotic treatment.

α2,3- Sialylation With&amp;nbsp;&amp;nbsp;Fucosylation&amp;nbsp;Associated with More Severe Anti-MDA5 Positive Dermatomyositis Induced by Rapidly Progressive Interstitial Lung Disease

α2,3- Sialylation With&amp;nbsp;&amp;nbsp;Fucosylation&amp;nbsp;Associated with More Severe Anti-MDA5 Positive Dermatomyositis Induced by Rapidly Progressive Interstitial Lung Disease

α2,3-Sialylation With Fucosylation&amp;nbsp;Associated With More Severe Anti-MDA5 Positive Dermatomyositis Induced by Rapidly Progressive Interstitial Lung Disease

α2,3-Sialylation With Fucosylation&amp;nbsp;Associated With More Severe Anti-MDA5 Positive Dermatomyositis Induced by Rapidly Progressive Interstitial Lung Disease

Subcutaneous Calcinosis in a Patient with Anti-MDA5 Positive Dermatomyositis.

Subcutaneous Calcinosis in a Patient with Anti-MDA5 Positive Dermatomyositis.

A novel CT scoring method predicts the prognosis of interstitial lung disease associated with anti-MDA5 positive dermatomyositis

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated interstitial lung disease (MDA5+ DM-ILD) is a life-threatening disease. This study aimed to develop a novel pulmonary CT visual scoring method for assessing the prognosis of the disease, and an artificial intelligence (AI) algorithm-based analysis and an idiopathic pulmonary fibrosis (IPF)-based scoring were conducted as comparators. A retrospective cohort of hospitalized patients with MDA5+ DM-ILD was analyzed. Since most fatalities occur within the first half year of the disease course, the primary outcome was the six-month all-cause mortality since the time of admission. A ground glass opacity (GGO) and consolidation-weighted CT visual scoring model for MDA5+ DM-ILD, namely ‘MDA5 score’, was then developed with C-index values of 0.80 (95%CI 0.75–0.86) in the derivation dataset (n = 116) and 0.84 (95%CI 0.71–0.97) in the validation dataset (n = 57), respectively. While, the AI algorithm-based analysis, namely ‘AI score’, yielded C-index 0.78 (95%CI 0.72–0.84) for the derivation dataset and 0.77 (95%CI 0.64–0.90) for the validation dataset. These findings suggest that the newly derived ‘MDA5 score’ may serve as an applicable prognostic predictor for MDA5+ DM-ILD and facilitate further clinical trial design. The AI based CT quantitative analysis provided a promising solution for ILD evaluation.

Forced vital capacity predicts the survival of interstitial lung disease in anti-MDA5 positive dermatomyositis: a multi-centre cohort study.

Anti-melanoma differentiation-associated gene 5 (MDA5) positive DM is a life-threatening disease often complicated with rapidly progressive interstitial lung disease (ILD). This study aimed to establish and validate a clinical prediction model for 6-month all-cause mortality in Chinese patients with anti-MDA5 positive DM-ILD. We conducted a retrospective observational study using a single-centre derivation cohort and a multicentre validation cohort. Hospitalized DM patients with positive anti-MDA5 antibody and ILD course ≤3 months on admission were included. Patients' baseline characteristics were described and compared between the deceased and survivors by univariable Cox regression. Optimal cut-off values were defined by the 'survminer' R package for significant continuous variables. Independent prognostic factors were determined by the final multivariable Cox regression model chosen by backward stepwise algorithm, which could be reproduced in both cohorts. The Kaplan-Meier survival analyses based on the derived predictor were conducted. A total of 184 and 81 eligible patients were included with a cumulative 40.8 and 40.7% 6-month mortality in the derivation and validation cohorts, respectively. Based on multivariable Cox regression, the prognostic factor at baseline was identified and validated as three-category forced vital capacity (FVC)%: FVC% ≥50%, FVC% <50%, unable to perform. This significantly distinguishes three risk stages with mortalities of 15.3, 46.8, 97.4% in the derivation cohort, and 14.9, 58.3, 86.4 in the validation cohort, respectively (all P<0.05). The validated FVC%-based categorical predictor in anti-MDA5 positive DM-ILD is helpful for risk stratification in clinical practice and might facilitate cohort enrichment for future trials.

Interstitial Lung Disease in Anti-MDA5 Positive Dermatomyositis.

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM) is a rare autoimmune disease predominantly reported in East Asia. MDA5+ DM is an intractable disease with impressively high mortality due to rapid-progressive interstitial lung disease (RPILD). Other typical clinical manifestations comprise DM-specific rash (Gottron's papules, heliotrope rash) and amyopathic/hypomyopathic muscle involvement. Multiple prognostic factors have been identified. Baseline forced vital capacity (FVC) %-based staging could serve as a simplified risk stratification system. Serum biomarkers including MDA5 Ab titers, ferritin, KL-6 levels, and CD4+CXCR4+ T cell percentage could provide additional surrogate value of ILD severity and treatment response, as well as potential predictive value for survival. Spontaneous pneumomediastinum (PNM), ground-glass opacity (GGO), and consolidation were demonstrated to be the most significant features in pulmonary high-resolution computed tomography (HRCT) findings of MDA5+ DM-ILD. The semi-quantitative assessment of lesions in HRCT has also been demonstrated relevant to the outcome. The current treatment of this disease is still largely empirical. Immunosuppressive treatments, i.e., "triple therapy" (combination of high-dose glucocorticoids, tacrolimus, and intravenous cyclophosphamide) and JAK inhibitor-based therapy, are the mainstream regimens for MDA5+ DM-ILD, supported by the recently published trials. However, more efficacious regimen with favorable safety profile and high-level evidence is still urgently demanded for patients with MDA5+ DM-ILD, especially those at advanced-stage. We will summarize the terminology, etiology and pathogenesis, clinical features and outcome, prognostic factors, and treatment of MDA5+ DM-ILD in this review.

2. Two cases of anti-MDA5 positive dermatomyositis with rapidly progressive interstitial lung disease

2. Two cases of anti-MDA5 positive dermatomyositis with rapidly progressive interstitial lung disease

A Phenotypical Case of Anti-MDA5 Positive Dermatomyositis

A Phenotypical Case of Anti-MDA5 Positive Dermatomyositis

MDA5-positive dermatomyositis: an uncommon entity in Europe with variable clinical presentations.

Clinically amyopathic dermatomyositis (CADM), described almost 50 years ago, is defined on the basis of still not validated criteria and characterized by skin findings almost without muscle weakness. Autoantibodies directed against the cytosolic pathogen sensor MDA5 (CADM 140) can mark this subtype of dermatomyositis which has been reported to associate, in particular ethnic groups, with severe progressive interstitial lung disease, poor prognosis and an hyperferritinemic status resembling hemophagocytic-like syndromes. MDA5 may be relevant in that Interferon-signature claimed to characterize inflammatory myopathies and dermatomyosits itself, but its role is not clear. However, the titre of anti-MDA5 autoantibodies seems to correlate with the outcome. In Caucasian populations the association between anti-MDA5 positive CADM and rapidly progressive interstitial lung disease seems to be weaker, but the limited numbers of patients described so far could explain the lack of statistical significance. As a fact, European patients with circulating anti-MDA5 autoantibodies may be clinically inhomogeneous and exhibit different rates of severity. The two patients affected by anti-MDA5 positive dermatomyositis described hereafter provide a clear example of the extreme variability of the disease in terms of laboratory findings and clinical features.