anti-MDA5 Antibody Research Articles

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis responds to rituximab therapy.

The purpose of this study was to assess the efficacy of rituximab (RTX) in the management of anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatomyositis (DM), with or without rapidly progressive interstitial lung disease (RP-ILD). Medical records of DM patients with anti-MDA5 antibodies treated with RTX therapy were reviewed retrospectively. Skin rash data, lung function tests, chest high-resolution computed tomography (HRCT), and serum markers were compared before and after RTX. Eleven consecutive cases, including 5 males and 6 females, were identified. One hundred percent of patients had a typical DM rash and about 45% presented with skin ulceration. All the patients had ILD, 73% had RP-ILD, and 27% had mild or asymptomatic ILD. Ro-52 antibodies were found in 55% of this group. Lymphopenia was present in 10/11 patients (91%). Around half (55%) had a level of ferritin greater than 1000ng/ml. Nine patients (82%) were refractory. These patients received intravenous RTX (375mg/m2) at 0 and 14days (conventional dose) or 100mg once a week for 4weeks (low dose). After RTX treatment, 2 patients (18%) with mild ILD showed complete remission, and 6 (55%) showed improvement in lung HRCT and/or lung function. Skin rash in 4 patients (100%) and ILD in 3 (75%) showed improvement in the low-dose group. Infection episodes occurred in four (57%) and one (25%) of the conventional-dose and low-dose group, respectively. Our study found that RTX is sufficient to improve skin rash and ILD or RP-ILD. Our results also suggest that lower RTX doses may be a useful therapy for anti-MDA5 antibody-positive DM patients. Key Points • To clarify efficacy of RTX in the management of anti-MDA5 antibody-positive DM, we performed a retrospective chart review of DM patients with anti-MDA5 antibodies who were treated with RTX. • This study found that RTX is sufficient to improve skin rash and ILD or RP-ILD. • The results suggest that low-dose RTX in treatment of MDA5-DM results in better responses and fewer adverse events.

Clinically Amyopathic Dermatomyositis with Interstitial Lung Disease Double-Positive for Anti-MDA5 and Anti-PL12 Antibodies

Clinically Amyopathic Dermatomyositis with Interstitial Lung Disease Double-Positive for Anti-MDA5 and Anti-PL12 Antibodies

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

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). 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. 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). 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.

The analysis of clinical phenotypes and autoantibodies in juvenile dermatomyositis

Objective: To elucidate the relationship between the myositis autoantibodies and clinical phenotypes of juvenile dermatomyositis (JDM). Methods: A total of 76 JDM patients admitted to the Children's Hospital of Chongqing Medical University from January 2017 to May 2020 were tested for myositis autoantibodies, including myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs). Kruskal-Wallis test and logistic regression were used to analyze the relationship between the antibodies and clinical characteristics. Results: In the 76 cases, 37 were females and 39 males. Forty-three cases (53%) were MSAs positive, among which the most common subtypes were autoantibodies against nuclear matrix protein 2 (NXP2) (15/76, 20%), melanoma differentiation-associated protein 5 (MDA5) (13/76, 17%) and transcription intermediary factor 1 gamma (9/76, 11%). While 20 cases (26%) were positive for MAAs, among which anti-Ro-52 antibody (17/76, 22%) was the most common subtype. Sixteen patients (21%) had both MAAs and MSAs. The incidences of arthritis (9 cases), fever (8 cases), skin ulcers (5 cases) and macrophage activation syndrome (MAS) (1 case) were significantly higher in the patients with anti-MDA5 antibody among the antibody groups. Dysphasia (6 cases) and edema (8 cases) mainly occurred in patients with anti-NXP2 antibody. Children with anti-MDA5 antibody were more likely to develop arthritis (OR=10.636, 95%CI: 2.770-40.844, P=0.001), skin ulcers (OR=12.500, 95%CI: 2.498-62.522, P=0.002), fever (OR=5.600, 95%CI: 1.580-19.849, P=0.008) and interstitial lung disease (ILD) (OR=23.333, 95%CI: 4.750-114.616, P<0.01). In the patients with different subtypes of MSAs, the creatine kinase value was significantly lower in the anti-MDA5 group than those in the anti-aminoacyl-tRNA synthetase (P=0.03), anti-NXP2 (P<0.01), and MSAs-negative group (P=0.013). Conclusions: Most children with JDM have positive myositis autoantibodies, and will present with different clinical phenotypes based on different autoantibodies. And children with anti-MDA5 antibodies are likely to develop ILD and MAS. Therefore the detection of myositis-specific autoantibodies is important.

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.

Anti-MDA5 antibody–positive dermatomyositis with rapidly progressive interstitial lung disease disguising as anti-synthetase syndrome

Anti-MDA5 antibody–positive dermatomyositis with rapidly progressive interstitial lung disease disguising as anti-synthetase syndrome

Cutaneous ulceration in a patient with amyophatic dermatomyositis anti-MDA5 antibody positive

Cutaneous ulceration in a patient with amyophatic dermatomyositis anti-MDA5 antibody positive

RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE IN ASSOCIATION WITH MDA5 ANTIBODY DERMATOMYOSITIS

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Clinically Amyopathic Dermatomyositis (CADM) is a subtype of dermatomyositis (DM) characterized by the presence of cutaneous lesions, without clinical evidence of muscle weakness. The presence of autoantibodies against Melanoma Differentiation-Associated protein 5 (MDA5) in this group is highly associated with rapidly progressive interstitial lung disease (RP-ILD) and a worse prognosis. We present a case of anti-MDA5 associated RP-ILD to illustrate the importance of screening for MDA5 in patients with CADM and DM. CASE PRESENTATION: Our patient was a 45-year-old woman with a history of hypothyroidism, seronegative inflammatory polyarthritis treated with hydroxychloroquine, and notably, a history of biopsy-proven DM with a negative myositis-specific antibodies (MSA) panel (which did not include MDA5 antibodies). She had been successfully treated for DM, and maintained in remission with oral steroids. Four years following the diagnosis of DM, she presented with insidious and gradually progressive dyspnea for over a year. Physical examination was unremarkable. Pulmonary function testing showed moderate restrictive lung disease. Chest X-ray was notable for bibasilar interstitial changes. Computed tomography (CT) scan of the chest revealed nonspecific, bilateral ground-glass opacities in the middle and lower lung zones, with associated bibasilar bronchiectasis in the affected areas (Figure 1). Bronchoscopic evaluation, including transbronchial biopsy, was performed, which was negative for malignancy or infection. Open lung biopsy was obtained via robotic-assisted thoracoscopy from the affected lobes, with histopathology revealing interstitial fibrosis with multiple fibrotic foci without clear evidence of honeycombing. The pattern was suggestive of usual interstitial pneumonia (UIP). Repeat testing for MSA revealed an elevated anti-MDA5 antibody level at 22 SI. The patient was consequently diagnosed with RP-ILD in conjunction with CADM, prompting the initiation of oral prednisone and azathioprine. DISCUSSION: Anti-MDA5 antibodies recognize the RNA helicase encoded by MDA5, a protein that is involved in innate immune processes. The presence of anti-MDA5 antibodies in patients with CADM has been linked to the presence of RP-ILD, and portends a poor prognosis. The mechanism of this autoantibody production is not fully understood. One meta-analysis found that the presence of these antibodies was 77% sensitive and 86% specific for the identification of RP-ILD. Additionally, anti-MDA5 antibodies can be utilized to predict clinical outcomes and monitor disease activity in these patients. Due to its high mortality rate from respiratory failure, immediate therapy with high-intensity combination immunosuppression is essential once the diagnosis is made. CONCLUSIONS: This case highlights the importance of screening for anti-MD5 antibodies in patients with CADM to elucidate their risk of developing RP-ILD. Reference #1: Li L, Wang Q, Yang F, et al. Anti-MDA5 antibody as a potential diagnostic and prognostic biomarker in patients with dermatomyositis. Oncotarget. 2017;8(16):26552–26564. doi:10.18632/oncotarget.15716 Reference #2: Chen, Z., Cao, M., Plana, M.N., Liang, J., Cai, H., Kuwana, M. and Sun, L. (2013), Utility of Anti–Melanoma Differentiation–Associated Gene 5 Antibody Measurement in Identifying Patients With Dermatomyositis and a High Risk for Developing Rapidly Progressive Interstitial Lung Disease: A Review of the Literature and a Meta-Analysis. Arthritis Care & Research, 65: 1316-1324. doi:10.1002/acr.21985 DISCLOSURES: No relevant relationships by Komal Ejaz, source=Web Response No relevant relationships by Dan Kazmierski, source=Web Response No relevant relationships by Bassel Noumi, source=Web Response No relevant relationships by Pius Ochieng, source=Web Response No relevant relationships by NISHANT SHARMA, source=Web Response No relevant relationships by Yichen Wang, source=Web Response

LATE DIAGNOSIS OF ANTI-MDA5 ANTIBODY-POSITIVE RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE WITH CUTANEOUS MANIFESTATIONS

SESSION TITLE: Medical Student/Resident Lung Pathology SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody is associated with rapidly progressive interstitial lung disease (RP-ILD). This can be seen in patients with clinically amyopathic dermatomyositis or more typical dermatomyositis. Not only is MDA5-positive RP-ILD a rare cause of ILD, but the ILD often results in significant morbidity and mortality. Although there are several proposed treatment regimens, patients often succumb to the illness despite initiation of therapy. As such, early diagnosis and treatment in these patients is of paramount importance. CASE PRESENTATION: Herein we report a case of 37-year-old male diagnosed with anti-MDA5-associated RP-ILD late in his clinical course. He presented in October 2019. He initially presented with marked unintentional weight loss, preceding episodes of antimicrobial-refractory pneumonia, and an upper thigh abscess prior to his transfer to our hospital. He had a complicated hospital course with profound multi-organ system failure. Given an unclear underlying diagnosis, empiric antimicrobials and corticosteroids were started and intensified, without improvement. Furthermore, his secondary acute respiratory distress syndrome did not respond to standard evidence-based strategies. In the setting of chest imaging suggestive of underlying ILD with profound pneumomediastium and concomitant Gottron papules, rheumatologic work-up revealed a unifying diagnosis very late in his hospital course. Despite mechanical ventilation, venovenous extracorporeal membrane oxygenation (VV-ECMO), high-dose steroids, intravenous immunoglobulin, and tacrolimus, the patient had little clinical response to his disease which ultimately proved fatal. DISCUSSION: To the best of our knowledge, this is one of the first cases where VV-ECMO was used to treat anti-MDA5 positive RP-ILD. Unfortunately, this case demonstrates the futility of supporting patients with anti-MDA5 positive RP-ILD with VV-ECMO, particularly when that support is initiated late in their clinical course. His hospital and pre-hospital course highlight the barriers of a healthcare system that ultimately could not save him. Moreover, this case illustrates the importance of early diagnosis and expedited trials of therapy. In the future, early diagnosis of anti-MDA5 positive RP-ILD may support the utility of VV-ECMO as a bridge to lung transplant. CONCLUSIONS: In a case such as this one, where the diagnosis eludes while irreversible lung disease progresses, ECMO is a therapeutic modality best avoided. We would further recommend, should ECMO be utilized in such cases, where the diagnosis has yet to be made, it is important that all parties involved are clear on the overall treatment plan to include when extracorporeal support will be withdrawn. Reference #1: Gonzalez-Moreno et al. Rapidly progressive interstitial lung disease due to anti-MDA5 antibodies without skin involvement: a case report and literature review. Rheumatology International 2018. 38:1293-1296. Reference #2: LeClair et al. Successful lung transplantation in a case of rapidly progressive interstitial lung disease associated with antimelanoma differentiation-associated gene 5 antibodies. Journal of Rheumatology 2018. 45:581-583. Reference #3: So et al. Rituximab for refractory rapidly progressive interstitial lung disease related to anti-MDA5 antibody-positive amyopathic dermatomyositis. Clinical Rheumatology 2018. 37:1983-1989. DISCLOSURES: No relevant relationships by Erika Anderson, source=Web Response No relevant relationships by Cyrus Askin, source=Web Response No relevant relationships by Carl Kay, source=Web Response No relevant relationships by Whittney Warren, source=Web Response

Circulating TFH cells is correlated with disease activity in anti-MDA5 antibody positive idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIM) are a group of disorders characterised by the production of autoantibodies and inflammatory infiltrates in the skeletal muscles. Follicular T helper (TFH) cells are known to be crucial for B cell differentiation and autoantibody production in autoimmune diseases. The aim of this study was to investigate the involvement of TFH cells in IIM. Circulating TFH cells in 44 IIM patients or 11 age- and gender-matched healthy controls (HCs) were measured by flow cytometry. ICOS, PD-1, active caspase-1 and Ki-67 expression in TFH cells was examined. The correlations between the frequency of TFH cells and clinical disease activities were also analysed. The frequency of TFH cells was 16.6% in IIM patients with anti-melanoma differentiation-associated gene (MDA5) antibody compared to 10.6% and 12.9% in anti-MDA5 negative patients or HCs, respectively (both p<0.05). The frequency of TFH cells was positively correlated with clinical disease activities: patient/parent's assessment VAS (r=0.51, p<0.05), physician's assessment VAS (r=0.59, p<0.05) and MYOACT scores (total systems: r=0.62, p<0.05; extramuscular system: r=0.56, p<0.05; pulmonary system, r=0.55, p<0.05). The percentage of PD-1highICOShigh TFH cells was 3.68% in anti-MDA5 positive patients compared to 2.70% and 1.96% in anti-MDA5 negative patients or HCs, respectively (both p<0.05). The percentage of Ki-67 positive TFH cells was 3.50% in anti-MDA5 positive patients compared to 2.36% and 1.76% in anti-MDA5 negative patients or HCs, respectively (p<0.05). Interestingly, active caspase-1 was significantly increased in TFH cells in anti-MDA5 positive patients compared to the patients without anti-MDA5 or HCs (3.30% vs. 1.67% and 3.30% vs. 1.02%, both p<0.001). These data suggest a role for TFH cells in the pathogenesis of anti-MDA5 positive IIM and TFH cells might serve as a disease biomarker for this subset of patients.

Anti-Ro52 antibody is an independent risk factor for interstitial lung disease in dermatomyositis

AimRecent studies have shown that anti-Ro52 antibody is associated with both interstitial lung disease (ILD) and the degree of disease severity in juvenile patients with dermatomyositis (DM). We found that more than half of adult patients with DM were positive for anti-Ro52 antibody. In this study, we analysed the correlation between anti-Ro52 antibody and ILD in adult patients with DM. MethodSerum samples were collected from 153 adult inpatients with DM, at the First Medical Centre of PLA General Hospital, Beijing, China, who met the classification criteria of idiopathic inflammatory myopathies from March 1, 2016 to September 30, 2019. The patients were followed up to May 31, 2020. Immunoblotting was used to detect 16 types of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) from serum samples. High-resolution computed tomography (HRCT) was used to calculate the ILD score, and tumours were screened. Clinical data and HRCT scores were evaluated and analysed retrospectively. ResultsOur results showed that anti-Ro52 antibodies were the most commonly found antibodies in patients with DM, with a positive rate of 52.9%. Anti-Ro52, anti-aminoacyl-tRNA synthetase (anti-ARS), and anti-melanoma differentiation-related gene 5 (anti-MDA5) antibodies were found to be risk factors for ILD development. Anti-Ro52 antibodies had a strong predictive effect on ILD in patients with DM. ConclusionThe occurrence of ILD is highly likely in patients with DM who are positive for the anti-Ro52 antibodies. Thus, anti-Ro52 antibodies is an independent risk factor for ILD in patients with DM.

Predictors and Mortality of Rapidly Progressive Interstitial Lung Disease in Patients With Idiopathic Inflammatory Myopathy: A Series of 474 Patients.

Objective: This study was conducted to identify the characteristics and prognosis of rapidly progressive interstitial lung disease (RP-ILD) in idiopathic inflammatory myopathy (IIM) and to assess the predictors for poor survival of RP-ILD in IIM.Methods: A total of 474 patients with IIM were enrolled retrospectively according to medical records from Peking University People's Hospital. Clinical and laboratory characteristics recorded at the diagnosis of patients with RP-ILD and chronic ILD (C-ILD) were compared. The Kaplan–Meier estimator and univariate and multivariate analyses were used for data analysis.Results: ILD was identified in 65% (308/474) of patients with IIM. Patients with ILD were classified into two groups based on lung features: RP-ILD (38%, 117/308) and C-ILD (62%, 191/308). RP-ILD resulted in significantly higher mortality in IIM compared with C-ILD (27.4 vs. 7.9%, P < 0.05). In this study, by comparing IIM patients with and without RP-ILD, a list of initial predictors for RP-ILD development were identified, which included older age at onset, decreased peripheral lymphocytes, skin involvement (periungual erythema, skin ulceration, and subcutaneous/mediastinal emphysema), presence of anti-MDA5 antibody, serum tumor markers, etc. Further multivariate Cox proportional hazards model analysis identified that anti-MDA5 positivity was an independent risk factor for mortality due to RP-ILD (P < 0.05), and lymphocytes <30% in BALF might also be associated with poor survival of myositis-associated RP-ILD (P < 0.05).Conclusion: Our study shows that RP-ILD results in increased mortality in IIM. Anti-MDA5 positivity and a lower lymphocyte ratio in BALF might be the predictive factor of mortality due to RP-ILD.

Classification of idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific antibodies

To investigate the classification of idiopathic inflammatory myopathies (IIM) based on clinical manifestations and myositis- specific antibodies using cluster analysis. We retrospectively analyzed the data of patients with IIM admitted in Nanfang Hospital in 2015-2019. The clinical data of the patients including serum creatine kinase (CK), interstitial lung disease (ILD), cancer, and myositis-specific antibodies were collected for two-step cluster analysis to identify the distinct clusters of patients, whose clinical characteristics were subsequently analysed. A total of 71 patients with IIM were included in this study, including 30 (42.3%) with polymyositis (PM), 20 (28.2%) with classic dermatomyositis (DM), 16 (22.5%) with amyopathic dermatomyositis (CADM), and 5 (7.0%) with immune-mediated necrotizing myopathy (IMNM). Two-step cluster analysis identified 3 distinctive subgroups: Cluster 1 of 15 (51.7%) patients characterized by rash, positive anti-MDA5 antibody and hypoproteinemia (P &lt; 0.05) with normal or slightly elevated CK level, mainly corresponding to CADM; Cluster 2 of 4 (57.1%) patients with significantly elevated CK and positive anti-SRP antibody (P &lt; 0.001) corresponding to IMNM; and Cluster 3 of 17 (48.6%) patients consisting primarily of patients with PM, characterized by positivity for anti- aminoacyl transfer RNA synthetases antibodies (P=0.022) corresponding to antisynthetase syndrome (ASS). Patients with IIM can be divided into 3 subgroups based on their clinical and serological characteristics (especially myositis-specific antibodies), and among them ASS may represent an independent IIM subgroup with unique clinical characteristics.

Prognostic evaluation of serum osteopontin in patients with anti-MDA5 antibody-positive dermatomyositis associated interstitial lung disease

BackgroundThe anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody was significantly associated with dermatomyositis associated with interstitial lung disease (DM-ILD) and poor survival in patients. However, there was no convenient and accurate biomarker can predict the poor prognosis of anti-MDA5 positive DM-ILD. This study aimed to evaluate the clinical significance of osteopontin (OPN) in anti-MDA5 positive DM-ILD patients. MethodsThe subjects were 43 patients diagnosed DM-ILD with anti-MDA5 antibody. The clinical data were obtained through a review of patient medical records. The serum samples were collected at the time of initial admission and detected for OPN concentrations and ferritin. In addition, immunohistochemistry analysis for OPN was performed on the lung sections of two patients with DM-ILD and six patients with early-stage lung cancer as normal control. ResultsThe median value of serum OPN in patients with anti-MDA5 positive DM-ILD was 1755.65 pg/ml. Immunohistochemical findings for OPN suggested that the expression of OPN in alveolar epithelial cells and macrophages of anti-MDA5-positive ILD patients was more obvious. Significant correlations between serum OPN and ferritin levels were observed (r = 0.317, P = 0.038). Although OPN and ferritin were both associated with mortality in Univariate Cox hazards analysis, OPN was an independent predictor of the prognosis of DM-ILD rather than ferritin in Multivariate Cox hazards analysis. ConclusionOPN can be expressed in lung tissues but also can exist as a secreted form in serum, and serum OPN may be a more valuable prognostic biomarker in DM-ILD patients with anti-MDA5 antibody than the serum ferritin.

IL-15 is a biomarker involved in the development of rapidly progressive interstitial lung disease complicated with polymyositis/dermatomyositis.

Polymyositis/dermatomyositis (PM/DM) is an autoimmune disease that is sometimes complicated with rapidly progressive interstitial lung disease (RPILD). However, serum and lung biomarkers that can predict RPILD development remain unclear. To determine potential serum and lung biomarkers that can predict RPILD development in patients with PM/DM-ILD. In total, 49 patients with PM/DM-ILD were enrolled. We measured the serum levels of 41 cytokines/chemokines, ferritin and anti-MDA5 antibody, compared them between the RPILD (n=23) and non-RPILD (n=26) groups, and ranked them by their importance through random forest analysis. To distinguish the two groups, we determined biomarker combinations by logistic regression analysis. We also measured the bronchoalveolar lavage fluid (BALF) levels of 41 cytokines/chemokines. Using immunohistochemistry, we examined IL-15 expression in lung tissues. The IL-15 production was also investigated using A549 and BEAS-2B cells. The RPILD group had significantly higher IL-15, IL-1RA, IL-6, CXCL10, VCAM-1, anti-MDA5 antibody and ferritin serum levels than the non-RPILD group, but it had a significantly low CCL22 level. Meanwhile, anti-MDA5 antibody, IL-15, CXCL8, CCL22, IL-1RA and ferritin were the best combination to distinguish the two groups. IL-15 and CCL22 were also predictive marker for RPILD development in anti-MDA5 antibody-positive patients. Additionally, the RPILD group had significantly high IL-15 levels in BALF. The lung tissues expressed IL-15, which increased after cytokine stimulation in the A549 cells. This study identified a combination of biomarkers predicting PM/DM-RPILD progression, and IL-15 is an important cytokine for predicting RPILD development and reflecting ILD severity.

903 The IgG1 isotype of anti-MDA5 antibody may dominate severity of interstitial lung disease in dermatomyositis

903 The IgG1 isotype of anti-MDA5 antibody may dominate severity of interstitial lung disease in dermatomyositis

The characteristics of lymphocytes in patients positive for anti-MDA5 antibodies in interstitial lung disease.

The aim was to investigate the characteristics of blood lymphocytes in patients positive for anti-melanoma differentiation-associated gene 5 antibodies (anti-MDA5+) in interstitial lung disease. Thirty-eight anti-MDA5+ patients with interstitial lung disease were admitted to our hospital, and the lymphocyte count, lymphocyte subtypes and lung high-resolution CT were recorded. Some of the cases were examined by bone marrow aspiration. Compared with the control group, the blood lymphocyte counts of anti-MDA5+ patients before treatment were significantly lower (P < 0.05). After treatment, lung interstitial lesions in some cases were reduced and the lymphocyte counts increased, whereas their CD4:CD8 ratio decreased (P < 0.05). In contrast, lung interstitial lesions of other cases were exacerbated after treatment and the lymphocyte counts decreased, whereas the CD4:CD8 ratio increased (P < 0.05). In cases with exacerbated lung interstitial lesions after treatment, there were fewer CD4 and CD8 Tcells than before treatment, and the change in CD8 Tcells was significant (P < 0.05). Bone marrow aspiration biopsy indicated that there was no abnormality in the distribution of bone marrow lymphocytes. Anti-MDA5+ patients showed a decrease in blood lymphocyte counts. The presence of anti-MDA5+ in patients with pulmonary interstitial lesions was positively correlated with blood lymphocyte counts but negatively correlated with the CD4:CD8 ratio. The CD8 Tcells decreased more significantly than CD4 Tcells in patients with aggravation of interstitial lung disease. The change in blood lymphocytes in anti-MDA5+ patients might be attributable to transfer of lymphocytes to the lungs to participate in the local immune response.

Evaluation of usefulness in surfactant protein D as a predictor of mortality in myositis-associated interstitial lung disease.

Surfactant protein D (SP-D) is considered a serum biomarker of various forms of interstitial lung disease (ILD). In this study, we examined the utility of SP-D as a predictive biomarker for mortality in patients with ILD associated with polymyositis/dermatomyositis (PM/DM) using large-scale multicentre cohort data. We enrolled 381 patients with incident PM/DM-associated ILD in a multicentre retrospective cohort based on the availability of serum SP-D at the baseline. Demographic and clinical characteristics as well as the presence of autoantibodies to melanoma differentiation-associated gene 5 (MDA5) and aminoacyl tRNA synthetase were measured at the time of diagnosis, and follow-up survival data were collected prospectively. Seventy-eight patients died during the median observation period of 18 months, and the majority of patients died of ILD. The SP-D levels at baseline were significantly lower (P = 0.02) in a non-survivor subset than in a survivor subset among the entire enrolled patients. However, the SP-D levels were higher in the non-survivor subset than in the survivor subset based on the stratification by anti-MDA5-positive, anti-ARS-positive and, double-negativity, although there was an only statistically significant difference (P = 0.01) in the double-negative group. Surprisingly, the SP-D levels were within the upper limit of normal, 110 ng/mL, in 54 (87%) of 62 anti-MDA5-positive patients who died. In the double-negative group, the mortality rates were significantly higher (P = 0.002) in a subset with SP-D ≥127.6 ng/mL, the cut-off value for mortality calculated by the receiver operating characteristic curve, than the other subset. All of patients with SP-D <127.6 ng/mL survived. Serum SP-D levels behave differently among patients with stratified by anti-MDA5 antibody, anti-ARS antibody and both negativity in PM/DM-associated ILD. Its use in clinical practice should be applied with caution on the basis of the presence or absence of anti-MDA5 antibody or anti-ARS antibody.

Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases.

The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease. To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data. Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis. Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.

AB0610 SEASONAL VARIATION IN IDIOPATHIC INFLAMMATORY MYOPATHIES INCIDENCE AND PRESENTATION: A RETROSPECTIVE STUDY IN BEIJING AND HONG KONG

Background:Seasonal patterns of disease onset and severity in idiopathic inflammatory myopathies (IIMs) as a whole are conflicting [1-3]. In recent years, over 10 myositis-specific antibodies (MSAs) have been identified. They are able to divide patients into homogenous subgroups and inform on prognosis [4].Objectives:The objective of the study was to investigate the seasonal variation of onset of IIMs characterised serologically.Methods:This was a multi-centred retrospective observational study. Consecutive Chinese patients with IIMs admitted to the rheumatology wards of the participating major regional hospitals in Beijing and Hong Kong from July 2013 to June 2018 were recruited. The diagnosis of IIMs was based on the Bohan and Peter’s criteria with definite or probable cases being included [5]. Patients with clinically amyopathic disease must have the typical Gottron’s papules or heliotrope rash as determined by rheumatologists or dermatologists, and with no symptoms or signs of muscle involvement according to Sontheimer [6]. Patients with juvenile myositis, inclusion body myositis, cancer-associated myositis and myositis associated with other connective tissue disease were excluded. A commercial line blot immunoassay kit (EUROLINE) was used to detect the MSAs.Results:All together 495 patients were studied. The mean age of the patients at disease onset was 48.1 years (S.D. 13.3). There was a female predominance (68.3%). The subgroups of IIMs were: dermatomyositis (61.0%), polymyositis (21.8%), clinically amyopathic dermatomyositis (12.9%), immune mediated necrotising myopathy (3.8%) and nonspecific myositis (0.4%). No particular seasonal pattern in disease onset was observed in IIM patients as a whole (Figure 1) or in any classical subgroups. However, significantly more patients with any one MSA had their disease started in the first half of the year (p=0.007) as shown in Figure 2. Patients with either anti-synthetase or anti-MDA5 antibodies, which are associated with interstitial lung disease, had more frequent disease onset from November to February, which might coincide with the local flu season. It was also found that MSA positivity was associated with infection of the patient (p=0.005). Further analyses showed that patients with MSAs which are typically associated with severe skin disease (MDA5, TIF1g, NXP2, SAE) had more hospitalisation from April to September where excessive sun exposure is expected. There were no major differences between the Beijing and Hong Kong subgroups.Conclusion:Apparent seasonal patterns were noticed in our ethno-serologically defined IIM patients. Certain environmental factors, particularly infection or UV exposure, could be potential triggers. Our findings could shed light on the identification of etiologic factors and enhance our understanding of disease pathogenesis.