anti-MDA5 Ab Research Articles

Clinical importance of anti-Ro52 antibody for polymyositis and dermatomyositis.

To clarify clinical features of anti-Ro52 antibody (Ab)-positive polymyositis (PM)/dermatomyositis (DM). We retrospectively examined clinical features and status of anti-Ro52 Ab in patients with PM/DM admitted at the University of Tsukuba Hospital between January 2019 and February 2023. We compared anti-Ro52 Ab-positive and -negative groups. A total of 40 patients were selected and analyzed. Median age at diagnosis was 61.5 (48.8-69.3) years and 34 cases were female. Twenty-three cases were PM and 17 cases were DM (including 6 clinically amyopathic dermatomyositis: CADM). Twenty-two cases were positive for anti-Ro52 Ab, 14 for anti-ARS Ab, and 6 for anti-MDA5 Ab. Interstitial lung disease (ILD) was detected in 29 cases, 9 of which were rapidly progressive. Glucocorticoid (GC)-resistant cardiomyopathy was detected in 6 cases, malignancy in 3 cases, and Sjögren's syndrome (SS) in 4 cases. Of the 22 anti-Ro52 Ab positive cases, only 3 were single-positive and the remaining 19 cases simultaneously had other autoantibodies. Comparing the anti-Ro52 Ab-positive and -negative groups, the frequencies of anti-ARS Ab positivity (63.6% vs. 0%), ILD (95.5% vs. 44.4%), GC-resistant cardiomyopathy (27.3% vs. 0%), concomitant use of immunosuppressants (95.5% vs. 55.6%), and levels of C-reactive protein (CRP) were significantly higher in the anti-Ro52 Ab-positive group (p<0.05). The frequencies of PM/DM, positivity of anti-MDA5 Ab, malignancies, and SS were comparable between groups. Anti-Ro52 Ab were frequently positive in PM/DM and anti-Ro52 Ab-positive patients showed significantly higher rates of anti-ARS Ab positivity and ILD, GC-resistant cardiomyopathy, concomitant use of immunosuppressants, and higher levels of CRP. Anti-Ro52 Ab may be useful as a severity marker in PM/DM.

Characteristics of anti-melanoma differentiation associated gene 5 antibody-positive dermatomyositis with thrombotic microangiopathy.

Anti-melanoma differentiation associated gene 5 antibody (anti-MDA5 Ab)-positive dermatomyositis (DM) is a representative of rapidly progressive interstitial pneumonia. However, its association with thrombotic microangiopathy (TMA), characterized by thrombocytopenia, haemolytic anaemia, and organ dysfunction, has not been defined. This study aimed to elucidate the characteristics of anti-MDA5 Ab-positive DM accompanied by TMA. We reviewed our hospital records from November 2009 to September 2022. We included patients in accordance with the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria and the criteria of Bohan and Peter. TMA was diagnosed according to the criteria for transplantation-associated TMA proposed by the International Working Group. This study enrolled a total of 26 anti-MDA5 Ab-positive DM patients, four of whom developed TMA. The patients with TMA had an increased urine protein/creatinine ratio. In addition, these four of them showed significantly elevated levels of ferritin and anti-MDA5 Ab titers and were considered to have high disease activity; yet, all of them survived. Our study indicated that anti-MDA5 Ab-positive DM patients with hyperferritinemia, a high anti-MDA5 Ab titer, and an increased urine protein/creatinine ratio should be carefully managed, bearing in mind a complication of TMA.

Antibodies against Serum Anti-Melanoma Differentiation-Associated Gene 5 in Rheumatoid Arthritis Patients with Chronic Lung Diseases

Chronic lung diseases (CLD), including interstitial lung disease (ILD) and airway diseases (ADs), are common complications of rheumatoid arthritis (RA). Rheumatoid factor (RF) and anti-citrullinated peptide antibodies are reported to be associated with CLD in RA patients. The presence of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies (Abs) is associated with clinically amyopathic dermatomyositis developing into rapidly progressive ILD. However, few studies on anti-MDA5 Abs in RA have been published. Here, we analyzed the association of anti-MDA5 Abs with CLD complications in RA. Anti-MDA5 Abs were quantified in sera from RA patients with or without CLD. Anti-MDA5 Ab levels were higher in RA patients with ADs than without (mean ± SDM, 4.4 ± 2.4 vs. 4.0 ± 4.2, p = 0.0001). AUC values of anti-MDA5 Ab and RF ROC curves were similar in RA patients with or without CLD (0.578, 95%CI 0.530-0.627 and 0.579, 95%CI 0.530-0.627, respectively, p = 0.9411). Multiple logistic regression analysis of anti-MDA5 Abs and clinical characteristics yielded an MDA5-index with a higher AUC value than anti-MDA5 Ab alone (0.694, 95%CI 0.648-0.740, p = 5.08 × 10-5). Anti-MDA5 Abs were associated with ADs in RA patients and could represent a biomarker for CLD, similar to RF. The involvement of anti-MDA5 Abs in the pathogenesis of ADs in RA is proposed.

Transcriptome Profiling of Immune Cell Types in Peripheral Blood Reveals Common and Specific Pathways Involved in the Pathogenesis of Myositis‐Specific Antibody‐Positive Inflammatory Myopathies

Idiopathic inflammatory myopathies (IIM) demonstrate characteristic clinical phenotypes depending on the myositis-specific antibody (MSAs) present. We aimed to identify common or MSA-specific immunological pathways in different immune cell types from peripheral blood by transcriptome analysis. We recruited 33 patients with IIM who were separated into the following groups: 15 patients with active disease at onset and 18 with inactive disease under treatment. All patients were positive for MSAs: anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) in 10 patients, anti-Mi-2 Ab in 7, and anti-aminoacyl-transfer RNA synthetase (ARS) Ab in 16. The patients were compared with 33 healthy controls. Twenty-four immune cell types sorted from peripheral blood were analyzed by flow cytometry, RNA sequencing, and differentially expressed gene analysis combined with pathway analysis. The frequencies of memory B cell types were significantly decreased in active patients, and the frequency of plasmablasts was prominently increased in active patients with anti-MDA5 Ab in comparison with healthy controls. The expression of type I interferon (IFN)-stimulated genes of all immune cell types was increased in the active, but not inactive, patients. Endoplasmic reticulum stress-related genes in all IIM memory B cells and oxidative phosphorylation-related genes in inactive IIM double negative B cells were also increased, suggesting prominent B cell activation in IIM. Furthermore, active patients with anti-MDA5 Ab, anti-Mi-2 Ab, or anti-ARS Ab were distinguished by IFN-stimulated and oxidative phosphorylation-related gene expression in plasmablasts. Unique gene expression patterns in patients with IIM with different disease activity levels and MSA types suggest different pathophysiologies. Especially, B cells may contribute to common and MSA-specific immunological pathways in IIM.

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

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

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

ObjectivesStudies 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.MethodsIn 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.ResultsSeventy-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.ConclusionMyocardial 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.

Monoclonal antibodies from B cells of patients with anti-MDA5 antibody-positive dermatomyositis directly stimulate interferon gamma production

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) positive dermatomyositis (anti-MDA5 DM) is a rare entity associated with poor prognosis and multiple immunologic abnormalities. These include the presence of autoAbs and deleterious interferon (IFN)-gamma production in the severe form of the disease. Here, we show that the autoAbs profile differs between patients, depending on disease severity, and that autoAbs from B cells of patients directly stimulate IFN-gamma production by peripheral blood cells. Serum of 29 anti-MDA5 DM patients were analyzed by indirect immunofluorescence (IIF) on Hep-2 cells, to identify patterns associated with poor outcome. Seventeen (59%) serum gave a specific cytoplasmic MDA5 pattern on Hep-2 cells, while 12 (41%) gave an unspecific pattern. Specific MDA5 pattern was associated with a higher risk to develop interstitial lung disease (p = 0.003). Monoclonal autoAbs were generated from B cell clones of two patients with extreme clinical presentation, one who developed a lethal form of the disease, and the other with a favorable outcome. Supernatants of the autoreactive B cell clones that gave an IIF cytoplasmic pattern were tested for their abilities to stimulate IFN-gamma production by peripheral blood cells. Out of 120,000 B cell clones analyzed, 12 produced monoclonal Abs that triggered direct IFN-gamma secretion by peripheral blood cells, by a monocyte-dependent mechanism. None of them was directed against the MDA5 antigen. Altogether, these findings demonstrated that autoAbs other than the highly specific anti-MDA5 Ab are direct contributors of the IFN-gamma upregulation that is linked to the severity of the disease.

Presence of Anti-MDA5 Antibody and Its Value for the Clinical Assessment in Patients With COVID-19: A Retrospective Cohort Study.

BackgroundStriking similarities have been found between coronavirus disease 2019 (COVID-19) and anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-related dermatomyositis, implying a shared autoinflammatory aberrance. Herein, we aim to investigate whether the anti-MDA5 Ab is present in COVID-19 and correlates with the severity and adverse outcome of COVID-19 patients.Methods and FindingsWe retrospectively recruited 274 adult inpatients with COVID-19 in this study, including 48, 164, and 62 cases of deaths, severe, and non-severe patients respectively. The anti-MDA5 Ab was determined by ELISA and verified by Western Blotting, which indicated that the positive rate of anti-MDA5 Ab in COVID-19 patients was 48.2% (132/274). The clinical and laboratory features, as well as outcomes between patients with positive and negative anti-MDA5 Ab were compared and we found that the anti-MDA5 Ab positive patients tended to represent severe disease (88.6% vs 66.9%, P<0.0001). We also demonstrated that the titer of anti-MDA5 Ab was significantly elevated in the non-survivals (5.95 ± 5.16 vs 8.22 ± 6.64, P=0.030) and the positive rate was also higher than that in the survivals (23.5% vs 12.0%, P=0.012). Regarding severe COVID-19 patients, we found that high titer of anti-MDA5 Ab (≥10.0 U/mL) was more prevalent in the non-survivals (31.2% vs 14.0%, P=0.006). Moreover, a dynamic analysis of anti-MDA5 Ab was conducted at different time-points of COVID-19, which revealed that early profiling of anti-MDA5 Ab could distinguish severe patients from those with non-severe ones.ConclusionsAnti-MDA5 Ab was prevalent in the COVID-19 patients and high titer of this antibody is correlated with severe disease and unfavorable outcomes.

P153 Characteristics of anti-melanoma differentiation-associated gene 5 positive dermatomyositis in Singapore

Abstract Background/Aims Anti-melanoma differentiation-associated gene 5 (MDA5) Ab positive associated dermatomyositis (DM) patients with rapidly progressive-interstitial lung disease (RP-ILD) have poor survival rates. The aim of this study was to determine the various characteristics in Singaporean patients with anti-MDA5-Ab associated DM. Methods A chart review was undertaken of 84 DM patients with positive myositis specific antibodies, diagnosed between January 2015 to July 2019, at a major tertiary centre in Singapore. All had confirmed probable or definite DM according to the Bohan and Peter criteria, and only those with an International Myositis Classification Criteria score of at least 55% (probable idiopathic inflammatory DM) were included. Results 18 out of 84 were anti-MDA5-Ab positive (See Table 1 for summary). Features more common in the anti-MDA5 Ab positive vs. the anti-MDA5 Ab negative cohort included: inverse Gottron’s papules (27.8% vs. 3%, p = 0.001) palmar papules (27.8% vs. 0%, p &amp;lt; 0.001), violaceous rash (55.6% vs. 16.7%, p = 0.001), cutaneous ulcers (66.7% vs. 6.1%, p = &amp;lt;0.001), clinically amyopathic DM (50% vs. 22.7%, p = 0.023) and polyarthritis (38.9% vs. 12.1%, p = 0.0009). The anti-MDA5 Ab positive cohort had a lower median creatine kinase (IU/L) versus the anti-MDA5 Ab negative cohort; 328 [60-3254] vs. 1318 [61-36776], (p = 0.0027). ILD was more common in the anti MDA5 Ab positive vs. anti-MDA5 Ab negative cohort (61.1% vs. 34.8%; p = 0.044). Of these anti-MDA5 Ab positive with ILD, 45.5% had RP-ILD, 27.3% had either chronic ILD or asymptomatic ILD respectively. In contrast, only 17.4% had RP-ILD in the anti-MDA5 Ab negative cohort. The mortality rate in the anti-MDA5 Ab positive vs. negative cohort was higher (33.3% vs. 24.2%). Patients with both Ro-52 and MDA5 Ab positivity had a higher incidence of cutaneous ulcers, pneumothorax, ILD and mortality. Of those anti-MDA5-Ab positive cases that survived, treatment included either rituximab and/or tofacitinib. Conclusion In our population, anti-MDA5 Abs associated DM is a distinct clinical subset of DM and associated with increased mortality. Better recognition of these distinct clinical features will enable early diagnosis, risk stratification and aggressive treatment to improve survival. Disclosure J. Low: None. C. Chua: None. W. Lim: None. L. Koh: None. M. Manghani: None.

Clinical manifestations and outcome of anti-aminoacyl-transfer RNA synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody positive patients with interstitial lung disease.

To analyse the clinical features and risk factors of acute/subacute interstitial pneumonia (A/SIP) and death in patients with positive anti-aminoacyl-transfer RNA synthetase antibody (anti-ARS Ab) and positive anti-melanoma differentiation-associated gene 5 antibodies (anti-MDA5 Ab). Interstitial lung disease (ILD) patients with anti-ARS+ or anti-MDA5+ were recruited. Their demographics, clinical manifestations, laboratory data were collected and they were followed up for 1 year. Risk factors of A/SIP and mortality were analysed. 71 patients with anti-ARS+ ILD and 31 patients with anti-MDA5+ ILD were included. Incidence of ulcerative rash, Gottron's sign, pulmonary infection and A/SIP in the anti-MDA5+ group were significantly higher than those in the anti-ARS+ group, Creatine kinase (CK), leukocyte count, and lymphocyte count were lower, the value of serum ferritin (SF) was higher, and 12-month cumulative survival rate was lower. Advanced age, anti-MDA5+ and low immunoglobulin G (IgG) level were independent predictors of A/SIP. The decreased PaO2 and elevated SF were independent predictors for poor prognosis in A/SIP patients. Compared to anti-ARS+ group, the anti-MDA5+ group was more prone to ulcerative rash, Gottron's sign and pulmonary infection. Patients with anti-MDA5+, advanced age and decreased values of IgG were more likely to have A/SIP, while patients with A/SIP had lower incidence of myositis and arthritis. Mortality of A/SIP patients increased with higher serum ferritin level.

A CASE SERIES OF RAPIDLY-PROGRESSIVE INTERSTITIAL LUNG DISEASE

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Rapidly progressing interstitial lung disease (RP-ILD) is a rare entity associated with poor outcomes. Anti-melanoma differentiation-associated protein 5 antibody (anti-MDA5 Ab) is strongly associated with RP-ILD. We report three cases with varying clinical features, treatment modalities, and outcomes. CASE PRESENTATION: Patient A was a 45-year-old man diagnosed with anti-MDA5 RP-ILD 8 months prior to admission. CT chest demonstrated diffuse peripheral reticulations and groundglass infiltrates without honeycombing in a non-specific interstitial pneumonia pattern. His disease progressed despite outpatient treatment with prednisone and mycophenolate, resulting in respiratory failure. Despite treatment with empiric antibiotics, high dose corticosteroids, IVIG, and rituximab his hypoxemia rapidly progressed to requiring mechanical ventilation and death. Patient B was a 32-year-old female diagnosed with RP-ILD after a 4-month history of arthralgias, facial rash, dyspnea, and recurrent pneumonias that did not improve with antibiotics. Chest CT demonstrated bilateral, multifocal consolidations in an organizing pneumonia pattern. Skin biopsy demonstrated dermatomyositis and surgical lung biopsy demonstrated a parenchymal inflammatory infiltrate of lymphocytes and plasma cells without fibrosis. Despite incremental treatment with high dose corticosteroids, IVIG, cyclophosphamide, and tacrolimus, she developed respiratory failure that quickly progressed to requiring mechanical ventilation and death. Patient C is a 38-year-old female who presented with several months of arthralgias, rash, and dyspnea. Chest CT demonstrated bilateral patchy groundglass and consolidative opacities with peripheral predominance in an organizing pneumonia pattern. Bronchoscopy with transbronchial biopsies demonstrated organizing pneumonia. Anti-MDA5 Ab titers were positive. Prednisone and mycophenolate mofetil for anti-MDA5 RP-ILD demonstrated clinical and radiographic improvement. She was switched to azathioprine and monthly IVIG due to hepatic toxicity but re-developed respiratory and liver failure due to hemophagocytic lymphohistiocytosis. She required mechanical ventilation and eventual tracheostomy. Treatment with anakinra and high dose steroids improved her respiratory failure and she was discharged. DISCUSSION: RP-ILD portends a poor prognosis with a 41% 6-month survival. Management is largely guided by case reports and expert opinion. Only 40% of patients will respond to corticosteroids alone. If mild and diagnosed early, mycophenolate or azathioprine, in addition to steroids, are first-line options. If severe or progressive, treatment with cyclophosphamide, rituximab, or a calcineurin inhibitor are recommended. Despite aggressive treatment, the disease still often progresses, as illustrated in patients A and B. CONCLUSIONS: Additional studies, including observational data, are needed to help guide management. Reference #1: Aoyama J, Hayashi H, Yajima C, et al. Anti-MDA5 antibody-positive rapidly progressive interstitial pneumonia without cutaneous manifestations. Respir Med Case Rep. 2019;26:193-196. Reference #2: Moghadam-kia S, Oddis CV, Sato S, Kuwana M, Aggarwal R. Anti-Melanoma Differentiation-Associated Gene 5 Is Associated With Rapidly Progressive Lung Disease and Poor Survival in US Patients With Amyopathic and Myopathic Dermatomyositis. Arthritis Care Res (Hoboken). 2016;68(5):689-94. Reference #3: Sakamoto N, Ishimoto H, Nakashima S, et al. Clinical Features of Anti-MDA5 Antibody-positive Rapidly Progressive Interstitial Lung Disease without Signs of Dermatomyositis. Intern Med. 2019;58(6):837-841. DISCLOSURES: No relevant relationships by Kelsey Black, source=Web Response No relevant relationships by Derrick Herman, source=Web Response No relevant relationships by Sai Krishna Korada, source=Web Response

Myositis-specific autoantibodies and their clinical associations in idiopathic inflammatory myopathies.

Myositis-specific autoantibodies (MSAs) have been found to be present predominantly in patients with idiopathic inflammatory myopathies (IIMs). This study aimed to investigate the prevalence of MSAs and their associated complications in a cohort of patients with IIMs. This was a multicentered prospective study. Consecutive adult Chinese patients with IIMs in the regional hospitals in Hong Kong were followed up from July 2016 to January 2018. Clinical characteristics, treatment history, and disease complications were documented. A commercially available immunoblot assay was used to detect the MSAs. Out of the 201 patients studied, at least one MSA was found in 63.2% of patients. The most common among the identified MSAs were the anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) and the anti-transcriptional intermediary factor 1-gamma antibody (anti-TIF1-γ Ab) (both 13.9%), followed by anti-Jo-1 antibody (12.4%). Anti-MDA5 was present exclusively in dermatomyositis (DM) and was strongly associated with digital ulcers, amyopathy, and rapidly progressive interstitial lung disease (RP-ILD). Anti-TIF1γ was strongly associated with refractory rash and malignancy. Independent risk factors of RP-ILD included anti-MDA5 (OR 14.5), clinically amyopathic DM (OR 13.9), and history of pulmonary tuberculosis (OR 12.2). Cox regression analysis showed that anti-TIF1γ (HR 3.55), DM (HR 3.82), and family history of cancer (HR 3.40) were independent predictors of malignancy. MSA testing enables dividing of patients with IIMs into phenotypically homogeneous subgroups and prediction of potentially life-threatening complications.

Long-term changes in nail fold capillary abnormalities and serum fibroblast growth factor 23 levels in dermatomyositis patients with anti-melanoma differentiating antigen 5 antibody.

Nail fold videocapillaroscopy (NVC) abnormalities are a characteristic finding of microangiopathy in dermatomyositis (DM). The aim of the present study was to examine long-term changes in NVC abnormalities and serum fibroblast growth factor 23 (FGF23) and vascular endothelial growth factor (VEGF) levels in DM patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab). Serum levels of FGF23 and VEGF were measured by enzyme-linked immunosorbent assay. NVC abnormalities were evaluated by capillaroscopy in 11 DM patients with anti-MDA5 Ab at baseline and after treatment. NVC abnormalities included irregularly enlarged capillaries, reduced capillaries, hemorrhages, capillary ramifications, disorganization of the vascular array, loss of capillaries and giant capillaries. Serum FGF23 levels were significantly decreased in patients with anti-MDA5 Ab (0.3±0.3pmol/L) compared with healthy controls (1.0±0.6pmol/L, P<0.01). Serum FGF23 levels significantly increased after treatment (0.3±0.3 vs 1.0±0.7pmol/L, P<0.005), but serum VEGF levels were comparable between at baseline and after treatment. At baseline, irregularly enlarged capillaries were observed in 10 of 11 patients, but after treatment, they were significantly reduced in only two (91% vs 18%, P<0.001). Hemorrhages were observed in all 11 patients at baseline, but disappeared in all after treatment (100% vs 0%, P<0.001). These results suggest that NVC abnormalities are reversible by treatment and that serum FGF23 levels reflect the degree of microvascular damage in DM patients with anti-MDA5 Ab.

Combined immunosuppressive therapy provides favorable prognosis and increased risk of cytomegalovirus reactivation in anti‐melanoma differentiation‐associated gene 5 antibody‐positive dermatomyositis

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) is myositis-specific autoantibody associated with rapidly progressive interstitial lung disease (ILD) and poor prognosis. In this retrospective observational study, we aimed to verify the efficacy and safety of introducing combined immunosuppressive therapy for anti-MDA5 Ab-positive dermatomyositis (DM) from their early stage. We recruited all Japanese patients diagnosed with DM in our clinic between January 2011 and October 2018, who had anti-MDA5 Ab, anti-aminoacyl transfer RNA synthetase Ab or anti-transcriptional intermediary factor 1-γ Ab. Combined immunosuppressive therapy was defined as combination of systemic corticosteroids, i.v. cyclophosphamide and tacrolimus. The difference of clinical features among the three groups was analyzed by multiple comparison analysis. The longitudinal change of the measurements from baseline was examined by Wilcoxon signed-rank test. Association between therapeutic regimens and adverse events was examined by logistic regression analysis. As a result, combined immunosuppressive therapy was most frequently used in the anti-MDA5 Ab-positive group, which significantly improved their forced vital capacity of the lung. Interval time since initial visit until starting treatment was the shortest in the anti-MDA5 Ab-positive group. There was no significant difference in the incidence of death and recurrence among the three groups. Cytomegalovirus reactivation was most common in the anti-MDA5 Ab-positive group, associated with combined immunosuppressive therapy. Collectively, early introduction of combined immunosuppressive therapy was effective for DM patients with anti-MDA5 Ab. At the same time, clinicians should be aware of the risk of cytomegalovirus reactivation during the treatment.

Research progress on amyopathic dermatomyositis associated with interstitial lung disease.

Research progress on amyopathic dermatomyositis associated with interstitial lung disease.

Serum neopterin as well as ferritin, soluble interleukin-2 receptor, KL-6 and anti-MDA5 antibody titer provide markers of the response to therapy in patients with interstitial lung disease complicating anti-MDA5 antibody-positive dermatomyositis

Objective: This study identified biomarkers that can be used to assess disease activity and response to therapy in patients with interstitial lung disease complicating anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-positive clinically amyopathic dermatomyositis (CADM).Methods: In 15 patients with interstitial lung disease complicating anti-MDA5 Ab-positive CADM, anti-MDA5 Ab, neopterin, interleukin (IL)-18, ferritin, and soluble interleukin 2 receptor (sIL-2R) levels were measured in cryopreserved serum specimens before and at multiple times after remission induction therapy, and their correlations were assessed.Results: Anti-MDA5 Ab, neopterin, IL-18, ferritin, and sIL-2R levels did not differ significantly between patients who survived and those who succumbed to the disease. In many cases, serum anti-MDA5 Ab titers were over the upper limit (over 150 index value) before treatment in the usual measuring method, and gradually decreased to the normal range at stable phase. Meanwhile, serum neopterin levels (21.6 [15.3–48.3] nmol/L) were significantly elevated in newly diagnosed patients and fell to 6.8 (5–11.4) nmol/L at 6 months after treatment introduction.Conclusions: Elevated serum neopterin as well as ferritin, sIL-2R, KL-6, and anti-MDA5 Ab titer might help identify patients with interstitial lung disease complicated with DM and might be useful in monitoring response to therapy.

Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis.

We aimed to determine the outcome of combination therapy with tofacitinib (TOF) in a case series of refractory rapidly progressive interstitial lung disease (ILD) associated with anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive (Ab+) DM. Patients who had poor prognostic factors and failed to respond to immunosuppressive therapy were selected for TOF treatment. Five patients with anti-MDA5 Ab+ DM-ILD who failed to respond to triple therapy with high dose glucocorticoids, CSA and CYC were given additional TOF (10 mg/day). To identify the poor prognostic factors, data from 15 consecutive patients (seven survived and eight died) with anti-MDA5 Ab+ DM-ILD before induction of TOF were analysed. Three poor prognostic factors were identified: serum ferritin level >1000 ng/ml before therapy; ground-glass opacities in all six lung fields before therapy; and worsening of pulmonary infiltrates during therapy. All six patients who had all of the three factors and received triple therapy died before TOF therapy. There were five patients who had all of the three prognostic factors and failed to respond to triple therapy, but were able to receive the combination therapy with TOF; among them, three survived and two died. The survival rate of patients who received TOF was significantly better than that of the historical controls with immunosuppressive therapy before TOF. The patients who received TOF experienced complicated adverse events, particularly viral infection. Combination therapy with TOF might have the potential to control refractory anti-MDA5 Ab+ DM-ILD.

Rituximab for refractory rapidly progressive interstitial lung disease related to anti-MDA5 antibody-positive amyopathic dermatomyositis.

To report our experience in using rituximab (RTX) for treating refractory rapidly progressive interstitial lung disease (RP-ILD) complicating anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab)-positive amyopathic dermatomyositis (ADM). Medical records of four ADM patients with refractory RP-ILD treated with RTX therapy were reviewed retrospectively. All four patients were tested positive for anti-MDA5 Ab and failed to respond to high-dose systemic steroid and other intensive immunosuppressive therapies. Respiratory symptoms, lung function tests, and high-resolution computed tomography (HRCT) of the chest were compared before and after the first course of RTX. After RTX treatment, all four patients had improvement in the respiratory symptoms in terms of New York Heart Association classification. Two patients successfully had their supplementary oxygen therapy weaned off. The lung function tests were significantly better in all patients. The HRCT showed improvement in three patients while the other one remained static. The recalcitrant vasculitic rashes associated with the anti-MDA5 Ab were also better in all patients. The average daily prednisolone dose dropped from 20 to 6.25mg post-treatment. None of the patients died throughout the follow-up period which ranged from 6months to 2years. However, two patients developed chest infection and one wound infection within 6months after the RTX infusion. Our results suggest that RTX may be a useful therapy for anti-MDA5 Ab-positive ADM associated with RP-ILD. However, infection is the major risk.

Successful treatment of plasma exchange for rapidly progressive interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis

Rationale:As the initial treatment of rapidly progressive interstitial lung disease (RPILD) with antimelanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab)-positive dermatomyositis (DM) patients, a combination of corticosteroids, cyclophosphamide, and calcineurin inhibitor is recommended. However, some of these patients have poor prognoses despite such intensive treatment. Other more effective treatments are desired. We report the case of an anti-MDA5 Ab-positive DM patient who had developed RPILD despite intensive treatments; she was treated successfully by a short-term plasma exchange (PE).Patient concerns:A 71-year-old Japanese woman was admitted to the rheumatology department of another hospital with progressive muscle weakness of the limbs and erythema on both upper eyelids and the fingers of both hands. She was suspected of having classical DM (CDM) based on the findings of typical skin and myositis. Although a chest computed tomography (CT) examination showed no findings of interstitial pneumonia at the first visit to the department, she newly presented interstitial pneumonia during her admission and her anti-MDA5 Ab titer was elevated.Diagnoses:She was diagnosed with interstitial lung disease (ILD) with anti-MDA5 Ab-positive DM.Interventions:She was treated with 1000 mg of methyl-prednisolone pulse, 500 mg of intravenous cyclophosphamide therapy (IVCY) followed by prednisolone 40 mg/day with tapering, and oral cyclosporine 200 mg/day. However, her interstitial pneumonia worsened with increasing breathing difficulty and an increasing serum ferritin level. She was transferred to our department, and we initiated PE as an additional treatment.Outcomes:After the PE treatment, all laboratory findings, for example, ferritin, KL-6, and the titer of anti-MDA5 Ab showed marked improvement, and the patient's skin symptoms and active interstitial pneumonia were relieved.Lessons:Our patient's case suggests that PE may be effective for RPILD in anti-MDA5 Ab-positive DM patients.

Neutrophil extracellular traps may contribute to interstitial lung disease associated with anti-MDA5 autoantibody positive dermatomyositis

In dermatomyositis (DM), anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody (autoAb) marks a subtype with low grade or absent muscle inflammation but frequent and rapidly progressive interstitial lung disease (ILD). The pathogenesis of ILD remains poorly unknown. The aim of the study is to explore whether neutrophil extracellular traps (NETs) are involved in the development of ILD in DM patients with anti-MDA5 autoAb. Patients with clinically amyopathic dermatomyositis (CADM, n=20), classic dermatomyositis (cDM, n=30), polymyositis (PM, n=20), and healthy controls (HC, n=20) were enrolled. Anti-MDA5 autoantibody and Krebs von den Lungen-6 (KL-6) were detected by ELISA. Circulating levels of NETs were assessed by the quantification of both serum cell-free DNA (cfDNA) and LL-37 (cathelicidin LL-37). Immunofluorescent staining was used to visualize NETs ex vivo. The elevated circulating NETs level was detected in DM patients with ILD complication. Compared to anti-MDA5 Ab- DM patients, anti-MDA5 Ab+ DM patients had the higher concentrations of serum cfDNA (293±69 vs 252±63ng/ml; P=0.035) and serum LL-37 (0.6±1.0 vs 0.2±0.2ng/ml; P=0.026). Positive correlations were established between serum levels of cfDNA and KL-6 in DM patients (r s=0.4422, P=0.0003). anti-MDA5 Ab+ sera, other than anti-MDA5 Ab- sera, could induce greater numbers of normal neutrophils to form NETs in vitro. These data suggest that aberrant NETs formation may be involved in the pathogenesis of ILD in DM patients with anti-MDA5 autoAb.