Rapidly Progressive Interstitial Lung Disease Patients Research Articles

Early Initiation of Plasma Exchange Therapy for Anti-MDA5+Dermatomyositis with Refractory Rapidly Progressive Interstitial Lung Disease.

Objectives Dermatomyositis (DM) is often associated with fatal anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive rapidly progressive interstitial lung disease (RP-ILD). RP-ILD often fails to respond to intensive treatment and has a poor prognosis. We examined the effectiveness of early plasma exchange therapy plus intensive treatment with high-dose corticosteroids and multiple immunosuppressants. Methods Autoantibodies were identified by an immunoprecipitation assay and enzyme-linked immunosorbent assay. All clinical and immunological data were collected retrospectively from medical charts. We divided patients into two groups based on treatment regimen: intensive immunosuppressive therapy alone as initial treatment (IS group) and early initiation of plasma exchange (PE) plus intensive immunosuppressive therapy (ePE group). Early PE therapy was designated if PE therapy was initiated within two weeks of starting treatment. Comparisons of the treatment response and prognosis between groups were performed. Patients Anti-MDA5-positive DM with RP-ILD was screened. Results Forty-four RP-ILD and DM patients had anti-MDA5 antibodies. Four patients were excluded because they died before receiving sufficient combined immunosuppressive therapy or before the evaluation of the immunosuppressive treatment effectiveness (IS, n=31; ePE, n=9). All 9 patients in the ePE group had improved respiratory symptoms and were alive, whereas 12 of 31 patients in the IS group died (100 vs. 61%, p=0.037). Of the 8 patients who had 2 values for a poor prognosis, indicating the highest risk for death using the MCK model, 3 of 3 patients in the ePE group and 2 of 5 in the IS group were alive (100 vs. 40%, p=0.20). Conclusion The early initiation of ePE therapy plus intensive immunosuppressive therapy was effective for patients with DM and refractory RP-ILD.

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

BackgroundAnti-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.MethodsPlasma 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).ResultsA 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.ConclusionThis 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.

Clinical features of macrophage activation syndrome in adult dermatomyositis:A single-center retrospective case-control study.

Little is known about the features of macrophage activation syndrome (MAS) in dermatomyositis, especially the association between rapidly progressive interstitial lung disease (RP-ILD) and MAS. To determine the characteristics of MAS in patients with dermatomyositis and their association with RP-ILD. This was a retrospective cohort study of 201 dermatomyositis patients at the First Affiliated Hospital of Zhejiang University over a 10-year period. A total of 22 (10.9%) patients were diagnosed with MAS. The rate of RP-ILD was significantly higher in patients with MAS than in those without MAS (81.8% vs. 17.4%, respectively, p < .001). Multivariate analysis indicated that RP-ILD (p = .019), ferritin level > 1685 ng/mL (p = .007) and hemoglobin < 100 g/L (p = .001) were independent risk factors for MAS. Furthermore, RP-ILD patients with MAS presented more cardiac injury (50.0% vs. 13.3%, respectively, p < .009), central nervous system dysfunction (42.8% vs. 3.4%, respectively, p < .001) and hemorrhage (38.9% vs. 3.3%, respectively, p = .003) than RP-ILD patients without MAS. The 90-day cumulative survival rate for patients with MAS was significantly lower than for those without MAS (18.2% vs. 82.1%, respectively, p < .001). MAS was a common and fatal complication of dermatomyositis in our cohort. MAS is closely related to RP-ILD in patients with dermatomyositis. When RP-ILD is present in dermatomyositis patients with abnormal laboratory findings, such as cytopenia and hyperferritinemia, the presence of MAS should be considered.

Interstitial Lung Disease in Dermatomyositis Without Myositis-Specific and Myositis-Associated Autoantibodies: Study of a Series of 72 Patients From a Single Cohort.

ObjectiveThe clinical features of interstitial lung disease (ILD) in patients with dermatomyositis (DM) and negative myositis autoantibodies had not been exactly demonstrated previously. This study aimed to describe and expand the phenotype of interstitial lung disease (ILD) in this cohort of patients.MethodsA total of 1125 consecutive Chinese patients with idiopathic inflammatory myopathies (IIM) between 2006 and 2020 were screened retrospectively. All proven cases of isolated ILD with both negative myositis-specific autoantibodies (MSA) and negative myositis-associated autoantibodies (MAA) were selected for inclusion. The clinical features and outcome among this group, MDA5+DM (DM patients with positive anti-MDA5 antibody) and ASS (patients with positive anti-aminoacyl tRNA synthetases antibodies were recorded and compared.ResultsOf 1125 IIM patients with an average follow-up of 6 years, 154 DM patients with negative MSA and MAA (MSA/MAA) were identified, with an ILD incidence of 46.8%. DM-ILD Patients with negative MSA/MAA presented younger age at onset (p<0.001), lower incidence of elevated CA153 (p=0.03) and fever (p=0.04)than those ILD patients with MDA5+DM and ASS.The estimated high-resolution computed tomography patterns of ILD showed non-specific interstitial pneumonia (66.6%), followed by organizing pneumonia in patients with negative MSA/MAA. OP pattern was more common in patients with MDA5+DM (69.7%), and the ratios of the OP (48.7%) and NSIP (51.3%) patterns were almost equal in patients with ASS. Of these DM-ILD patients with negative MSA/MAA, 25% developed rapidly progressive interstitial lung disease (RP-ILD). Patients with RP-ILD had a shorter disease duration (p=0.002), higher percentage of positive ANA(p=0.01) and organizing pneumonia patterns (p=0.04), elevated CYFRA211(p=0.04) and decreased FiO2/PaO2 (p<0.001) than those with chronic progressive ILD. The incidence of OP pattern in RP-ILD patients with negative MSA/MAA was lower than in those RPILD patients with MDA5+ DM (75%) and ASS (89%) (p=0.006). The cumulative 5- and 10-year survival rates in the DM-ILD patients with negative MSA/MAA were 91% and 88%, respectively, during the long-term follow-up study. And they had more favorable survival rate compared with ILD patients with MDA5+DM and ASS (p<0.001). An independent prognostic factor was identified as decreased PaO2/FiO2 (hazard ratio, 0.97; p=0.004].ConclusionsThis study indicates DM-ILD patients with negative MSA/MAA had favorable long-term outcomes. Decreased baseline PaO2/FiO2 acted as an independent prognostic factor for this group of 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.

POS0879 CLINICAL FEATURES, PROGNOSTIC FACTORS, AND OUTCOME OF ANTI-MDA5 POSITIVE DERMATOMYOSITIS WITH RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE: A MULTICENTER STUDY OF 238 PATIENTS

Background:Anti-melanoma differentiation-associated gene 5 positive dermatomyositis (anti-MDA5+ DM) is typically amyopathic and associated with a life-threatening, therapy-resistant, rapidly progressive interstitial lung disease (RP-ILD).Objectives:The present study aims to characterize the prognostic factors and long-term outcome of MDA5+ DM -associated RP-ILD.Methods:A multicenter retrospective study was performed across ten tertiary hospitals in China between January 1, 2018 to December 31, 2019.Results:A total of 238 patients (170 women) with MDA5+ DM enrolled into this retrospective clinical study. The mean age was 53.0 ± 12.2 years. The median follow-up duration was 6.3 ± 12.2 months. Of those 238 anti-MDA5+ patients, ILD is commonly observed in 213 patients, and RP-ILD occurred in 35.29% (84/213) of these patients (RP-ILD defined as progressive dyspnea occurs within 1 month after the onset of respiratory symptoms, and chest radiography or pulmonary function test show progressive interstitial abnormalities). The mortality rate of RP-ILD patients within the 6 months was 58.3% (49/84) in our cohort. Death peaked the first three months after diagnosis, occupying 84.8% (39/46) of died RP-ILD patients. Cox univariate proportional hazard analysis showed that age, gender, disease duration, abnormal laboratory features (LDH, CK, ESR and CRP), anti-Ro52 autoantibody and anti-MDA5 grade were related to the risk of occurrence of RP-ILD in patients with MDA5+ DM. The Cox proportional hazards model identified the disease duration [odds ratio (OR) 0.81 (95% CI 0.68, 0.96), P=0.016] as a protective factor, and anti-Ro52 autoantibody [OR 5.82 (95% CI 1.72, 19.73), P=0.005] as independent risk factors for the occurrence of RP-ILD in MDA5+ DM patients. The 6-month all-cause mortality rate of RP-ILD patients was 58.3% (49/84).Conclusion:Combined with anti-Ro52 in Myositis-specific antibodies was associated with the occurrence and long-term mortality in MDA5+ DM -associated RP-ILD patients. The results suggest poor overall survival among patients with MDA5+ DM -associated RP-ILD. Survival during the first 6 months is crucial for long-term survival. Early recognition and prompt treatment of this high-risk group of MDA5+ DM -associated RP-ILD patients are therefore important.Disclosure of Interests:None declared

Predictors of Poor Outcome of Anti-MDA5-Associated Rapidly Progressive Interstitial Lung Disease in a Chinese Cohort with Dermatomyositis.

Objective Antimelanoma differentiation-associated protein 5 (anti-MDA5) autoantibody has been reported in dermatomyositis (DM) to be associated with rapidly progressive interstitial lung disease (RP-ILD). Our study is aimed at determining the clinical characteristics and prognostic factors underpinning anti-MDA5-associated RP-ILD. Methods Patients with anti-MDA5-associated DM (aMDA5-DM) were identified at the Peking University People's Hospital. The presence of anti-MDA5 antibody was determined by immunoblotting. Kaplan-Meier, chi-square test, univariate, and multivariate data analyses were used. Results Out of 213 patients with DM and clinically amyopathic dermatomyositis (CADM), 20.7% (44/213) of patients were identified as aMDA5-DM. Amongst the aMDA5-DM patients, 63.6% (28/44) were identified as having anti-MDA5-associated RP-ILD. During the follow-up, 32.1% (9/28) of patients with anti-MDA5-associated RP-ILD died of respiratory failure. We identified older age and periungual erythema as two independent risk factors for RP-ILD mortality. Age ≥ 57 years at disease onset was significantly associated with poor survival (P = 0.02) in patients with anti-MDA5-associated RP-ILD, while patients with periungual erythema had a better survival rate than those without periungual erythema (P < 0.05). Conclusions Anti-MDA5-associated RP-ILD is significantly associated with poor survival rates in DM/CADM patients. More effective intervention should be administered to anti-MDA5-associated RP-ILD patients, especially to senior patients and those without periungual erythema.

Successful treatment of anti-MDA5 antibody-positive refractory interstitial lung disease with plasma exchange therapy.

We examined the effectiveness of plasma exchange (PE) therapy to reduce the mortality of rapidly progressive interstitial lung disease (RP-ILD) in patients positive for anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. Among 142 patients newly diagnosed with PM/DM or clinically amyopathic DM from 2008 to 2019 at our hospital, 10 were diagnosed with refractory RP-ILD and were positive for anti-MDA5 antibodies. PE was used as an adjunct to standard therapy and consisted of fresh frozen plasma as replacement solution. The primary outcome was non-disease-specific mortality. Anti-MDA5 antibodies were detected in 28 patients, of whom 21 were diagnosed with RP-ILD and 10 were refractory to intensive immunosuppressive therapy. Six patients received PE (PE group) and four did not (non-PE group). The 1-year survival rate of the PE group was higher than that of the non-PE group (100% and 25%, respectively, P = 0.033). Regarding adverse events associated with PE, two patients had anaphylactic shock, one had high fever due to fresh frozen plasma allergy and one had a catheter infection. All adverse events resolved with appropriate treatment. We evaluated the association between 1-year survival rate and PE for refractory RP-ILD in patients positive for anti-MDA5 antibodies. Intensive immunosuppressive therapy improved the survival rate in RP-ILD patients with anti-MDA5 antibodies, but 20-30% of cases were still fatal. PE could be administered to patients with active infectious disease who were immunocompromised by intensive immunosuppressive therapy. PE may be considered in refractory RP-ILD patients positive for anti-MDA5 antibodies.

Interstitial Lung Disease with Anti-melanoma Differentiation-associated Protein 5 Antibody: Rapidly Progressive Perilobular Opacity.

Objective Rapidly progressive interstitial lung disease (RP-ILD) with anti-melanoma differentiation-associated protein 5 (MDA5) antibody potentially presents with a fatal clinical course and requires early intensive treatment. Recently, perilobular opacity was reported to pathologically correspond to the acute phase of diffuse alveolar damage in RP-ILD with anti-MDA5 antibody. We aimed to investigate whether or not perilobular opacity was a common radiological finding in RP-ILD patients with anti-MDA5 antibody. Methods We conducted a retrospective review of the medical records of eight consecutive patients with RP-ILD with anti-MDA5 antibody. The clinical features and radiological findings of follow-up computed tomography (CT) during the course of their disease were evaluated. Results Among eight RP-ILD patients with anti-MDA-5 antibody, six showed perilobular opacity in the lower lobes, and the remaining two had only consolidation on high-resolution CT. Of note, the perilobular opacity in all six patients thickened and progressed to consolidation with a loss of lung volume in a short period. Despite intensive treatment, 6 patients (75%) died within 100 days after the first visit. Notably, the two patients with consolidation presented with a very rapid clinical course and died in 13 days each. In the two survivors, the perilobular opacity and consolidation recovered with improvement in the loss of lung volume. Conclusion Rapidly progressive perilobular opacity that thickens and progresses to consolidation is characteristic of RP-ILD with anti-MDA5 antibody. Chest physicians should immediately check the status of anti-MDA-5 antibody in order to initiate early aggressive therapy in RP-ILD patients with rapidly progressive perilobular opacity.

Multiple values of 18F-FDG PET/CT in idiopathic inflammatory myopathy.

This study aimed to investigate the multiple values of 18F-FDG PET/CT in detecting malignant tumors, evaluating myopathy, and determining interstitial lung disease in patients with idiopathic inflammatory myopathy (IIM). We retrospectively analyzed the data of 38 patients who were examined by 18F-FDG PET/CT and eventually diagnosed as IIM. We also collected the data of another 22 cases with negative PET/CT as the control. Pulmonary HRCT images were acquired simultaneously with regular 18F-FDG PET/CT imaging for each patient. Image analysis included the presence of malignant lesions, muscular FDG uptake, and interstitial lung disease and its imaging features. IIM was classified into polymyositis (PM), classic dermatomyositis (CDM), and clinical amyopathic dermatomyositis (CADM). All suspected malignant lesions were confirmed by histopathological examination. Interstitial lung disease was diagnosed by HRCT. Rapidly progressive interstitial lung disease (RP-ILD) was determined according to clinical follow-ups. The significance of 18F-FDG PET/CT in the detection of malignancy, observation of activity of myopathy, and determination of interstitial lung disease in IIM patients was explored based on the final clinical diagnosis. In the 38 patients with IIM, 3 cases were classified as PM, 18 as CDM, and 17 as CADM. PET/CT correctly detected 7 cases (18.4%) of malignant tumors, and all of which were found in CDM and PM patients. The muscular FDG uptake in IIM patients was higher than the control population, and it was higher in patients with myopathy (including PM and CDM) than in patients with CADM. The muscular FDG uptake in IIM patients was correlated with elevated serum creatine kinase level (r=0.332, P=0.042) and impaired muscle strength (r=-0.605, P<0.001). Interstitial lung disease was detected by HRCT in 30 patients (78.9%), and 7 of them were eventually confirmed as RP-ILD, according to the clinical outcome. The FDG uptake in lung lesions of RP-ILD patients was higher than those with chronic interstitial lung diseases, even though no significant difference was found between the CT features of RP-ILD and chronic interstitial lung disease. When SUVmax≥2.4 was employed as the threshold for RP-ILD prediction, the diagnostic efficiency was yield with a sensitivity of 100.0% (7/7), specificity of 87.0% (20/23), and accuracy of 90.0% (27/30), respectively. For IIM patients, 18F-FDG PET/CT has multiple values in identifying malignancies, observing the status of inflammatory myopathy, detecting interstitial lung disease, and predicting the occurrence of RP-ILD. Therefore, it is recommended to use PET/CT in the clinical course of diagnosis and management of IIM.

Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis

The aim of this study was to investigate the precise clinical characteristics and to analyse the association between the anti-MDA5 antibody (anti-MDA5ab) titre and disease status in patients with anti-MDA5ab-positive DM. Twenty-seven patients who presented with DM and were positive for the anti-MDA5ab were enrolled. The association between the clinical manifestations and the clinical parameters, including the anti-MDA5ab, was analysed. The complication of rapidly progressive interstitial lung disease (RP-ILD) occurred in 20 (74%) patients. The frequencies of fatal outcome, relapse and malignancy were 33, 4 and 4%, respectively. Remarkably, a fatal outcome occurred within the first 6 months. Compared with six non-RP-ILD patients, elderly age at onset, severely involved pulmonary function and high levels of serum ferritin were present in 20 RP-ILD patients with anti-MDA5ab. Alveolar-arterial oxygen difference (AaDO(2)) ≥32 mmHg and ferritin ≥828 ng/ml at admission were poor prognostic factors in RP-ILD patients with anti-MDA5ab-positive DM. The median value of the anti-MDA5ab titre on admission was higher in patients who later died than in those who survived. The efficacy of treatment was indicated by the anti-MDA5ab, ferritin and IL-18 concentrations. The decline index of the anti-MDA5ab titre after treatment was lower in the subset of patients who died than in the subset of patients who lived. Sustained high levels of anti-MDA5ab, ferritin and IL-18 were present in the patients who died. Anti-MDA5ab titre and ferritin and IL-18 concentrations are useful for the evaluation of the response to treatment and the status of ILD in patients with anti-MAD5ab-positive DM.