Soluble CD206 levels correlate with disease deterioration and predict prognosis of anti-MDA5 antibody-positive dermatomyositis related interstitial lung disease

Introduction

The prognosis of anti-MDA5 antibody-positive dermatomyositis/clinically amyopathic dermatomyositis-associated interstitial lung disease (MDA5-DM/CADM-ILD) is poor. This study was to evaluate the effect of serum soluble CD206 (sCD206), a biomarker of macrophage activation, on predicting the interstitial lung disease (ILD) deterioration and prognosis for MDA5-DM/CADM-ILD.

Methods

Forty-one patients diagnosed with MDA5-DM/CADM-ILD were retrospectively included. The clinical data were analyzed. Serum sCD206 levels were measured in 41 patients and 30 healthy controls. The relation between sCD206 levels and ILD deterioration was assessed. Receiver operating characteristic (ROC) curve was generated to determine the optimal cut-off value of sCD206 for predicting outcome. The association between sCD206 and survival was examined.

Results

The median serum sCD206 level in patients was significantly higher than healthy controls (464.1 ng/mL vs. 349.1 ng/mL, P = 0.002). In DM/CADM patients, the sCD206 level was significantly higher in patients with acute/subacute interstitial lung disease (AILD/SILD) than those with chronic interstitial lung disease (CILD) (539.2 ng/mL vs. 309.4 ng/mL, P = 0.005). The AUC of sCD206 was 0.885 for predicting mortality (95% CI 0.779–0.990). Patients were divided into two groups: sCD206 high level group (≥400 ng/mL) and sCD206 low level group (<400 ng/mL). Patients with sCD206 high level had significantly decreased survival rate than those with low level (25% vs. 88%, P < 0.001). The adjusted hazard ratio of sCD206 for mortality was 1.003 (adjusted for age and gender, P < 0.001), with sCD206 high level associated with higher death risk (HR 4.857, P = 0.006).

Conclusion

Serum sCD206 might be a potential predictor of ILD deterioration and prognosis for Chinese patients with MDA5-DM/CADM-ILD.     

Anti‐MDA5‐associated dermatomyositis

Anti‐MDA5‐associated dermatomyositis (MDA5‐associated DM) is an uncommon presentation of idiopathic inflammatory myositis, typically amyopathic, associated with rapidly progressive, treatment refractory interstitial lung disease and poor prognosis, particularly in patients with concomitant rapidly progressive interstitial lung disease (RP‐ILD). We report two cases of MDA5‐associated DM with fatal outcome in one of the patients, despite ‘aggressive triple therapy’ for RP‐ILD.     

皮肌炎合并间质性肺疾病患者的临床特征分析

目的探讨皮肌炎(dermatomyositis,DM)合并间质性肺病(interstitial lung disease,ILD)患者的临床特点,以提高对DM-ILD的认识。方法搜集南京鼓楼医院自2006年6月至2013年6月期间临床确诊、资料完整的皮肌炎患者91例,对其中39例DM-ILD患者的临床特点及影像学检查进行分析。结果 91例患者中有间质性肺病者39例(42.8%),DM-ILD组发病年龄及病程与DM-无ILD组比较无明显差别(P0.05);DM-ILD组更常出现雷诺现象、关节痛、低热、咳嗽、咳痰及呼吸困难;DM-ILD组血沉(ESR)明显增快,C反应蛋白(CRP)明显增高,两组比较差异均有统计学意义(P0.01);抗核抗体(ANA)、乳酸脱氢酶(LDH)在两组间无明显差异,DM-ILD组抗Jo-1抗体阳性率增高;肺功能检查示DM-ILD组以限制性通气功能障碍及弥散功能障碍为主,DM-无ILD组肺功能正常;DM-ILD组胸部CT改变以磨玻璃影、条索状影及网格样改变最常见,胸腔积液少见;DM-ILD可增加死亡风险达2.3倍,感染是最常见的死亡原因。结论 ILD是DM常见的系统损害,DM-ILD的发生与疾病的活动及某些自身抗体有关,严重影响疾病预后,因此确诊DM的患者均应进一步明确肺部病变情况。     

血清可溶性细胞间黏附分子-1在皮肌炎合并间质性肺病患者中的意义研究

目的 探讨血清可溶性细胞间黏附分子1 (sICAM-1)在皮肌炎合并间质性肺病(ILD)患者中的意义.方法 回顾性分析中国医科大学附属第一医院2018年1月至2020年2月50例确诊为皮肌炎的患者,按是否合并ILD分为ILD组和非ILD组.收集研究对象的临床资料并使用酶联免疫吸附测定(ELISA)法测量血清sICAM-...     

Anti-MDA5 antibody dermatomyositis-associated rapidly progressive interstitial lung disease patient complicated with mixed connective tissue disease: A case report

Anti-MDA5 antibody dermatomyositis (DM) is a special type of myositis, which can potentially cause rapidly progressive interstitial lung disease (RP-ILD). Mixed connective tissue disease (MCTD) is a complex disease with different characteristics of autoimmune connective tissue disease, associated with ILD. Both are rare diseases, and few patients with both diseases have been reported. A 71-year-old woman complained of palpitations, with a 2 months history of rash around her hands, extensor surface of right elbow, and the nape of her neck. Subsequently, the patient had acute exacerbation of dyspnea and tachypnea. Anti-Ro52, U1 RNP and MDA5 antibodies were positive; the presenting evidence was suggestive of anti-MDA5⁺DM-RP-ILD complicated with MCTD. Our patient deteriorated rapidly and had a fatal outcome, despite “triple therapy” for RP-ILD. This case illustrates that patients with coexisting anti-MDA5⁺DM and MCTD have the former's typical clinical manifestations, and may develop ILD quickly rather than slowly as in MCTD, especially with the coexistence of anti-Ro52 antibodies.     

KL-6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis

Abstract. Fathi M, Barbasso Helmers S, Lundberg IE (Karolinska University Hospital, Stockholm; Karolinska Institutet, Karolinska University Hospital, Stockholm; and Institute of Environmental Medicine, Karolinska Institutet, Stockholm; Sweden). KL‐6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis. J Intern Med 2012; 271 : 589–597. Objectives. To investigate whether Caucasian patients with polymyositis (PM) or dermatomyositis (DM) and interstitial lung disease (ILD) have elevated serum levels of KL‐6 compared with patients without ILD and whether KL‐6 could be used as a marker for ILD activity and treatment efficacy of ILD in PM/DM. Design and methods. Thirty patients with PM/DM (seven with ILD) and 17 age‐ and sex‐matched healthy controls were included in a retrospective, cross‐sectional analysis. Twelve patients were followed for longitudinal evaluation. ILD was defined as restrictive lung function impairment with radiographic signs of ILD. Serum KL‐6 levels were measured using a sandwich enzyme immunoassay kit. Groups were compared by Mann–Whitney U‐test. Results. PM/DM patients with ILD had significantly higher median serum KL‐6 levels compared with those without ILD: 995 (range 533–2318) versus 322 (range 132–1225) U mL^?1 (P = 0.0002). Median serum levels of healthy controls were 225 (range 136–519) U mL^?1. Serum levels of KL‐6 were inversely correlated with percentages of forced expiratory volume in 1 s (FEV₁), vital capacity (VC), total lung capacity (TLC), forced VC, diffusing capacity of carbon monoxide (DLco), maximal voluntary ventilation at 40 breaths min^?1 and residual volume (RV). Changes in KL‐6 levels showed a significant inverse correlation with changes in percentage FEV₁, TLC, DLco and RV. At a cut‐off level of 549 U mL^?1 (mean ± 2.5 SD for controls), the sensitivity and specificity for diagnosis of ILD were 83% and 100%, respectively. Conclusion. The level of serum KL‐6 may serve as measure of ILD in patients with PM/DM and is a promising biomarker for use in clinical practice to assess clinical response to treatment.     

无肌炎性皮肌炎引起急性肺间质病变2例并文献复习

目的提高对无肌炎性皮肌炎引起的急性肺间质病变（ADM—ILD）的临床表现诊断及治疗的认识。方法报道1例死亡及1例成功救治的无肌炎性皮肌炎引起的急性肺间质病变,并结合国内文献报道35例ADM—ILD患者的临床资料进行分析。结果临床上表现为胸闷、气促、干咳、发热、进行性呼吸困难、紫绀,并很快到严重的低氧血症和呼吸衰竭,高分辨率CT有很大的诊断价值。治疗效果欠佳。结论无肌炎性皮肌炎引起的急性肺间质病变死亡率很高,临床治疗过程中应该引起重视。     

Successful delivery in a patient with clinically amyopathic dermatomyositis during pregnancy despite first-trimester acute exacerbation of interstitial lung disease

A 37-year-old woman with rheumatoid arthritis and interstitial lung disease (ILD) developed clinically amyopathic dermatomyositis (CADM) after achieving pregnancy through in vitro fertilization. She was given oral prednisolone, which improved her respiratory status, and delivered a healthy baby at 35 weeks’ gestation. There are few reports of successful outcomes for CADM during pregnancy; to the best of our knowledge, this is the first report of successful delivery in a patient with both CADM and ILD.     

Mycophenolate mofetil therapy for rapidly progressive interstitial lung disease in a patient with clinically amyopathic dermatomyositis

Abstract

Background Though concern of hepatitis B virus (HBV) reactivation by antirheumatic agents has limited therapeutic opportunities in HBV-infected rheumatoid arthritis (RA) patients, the relative risks (RR) among such agents have not been clarified.

Objective We compared the reporting of antirheumatic-agent-associated hepatitis B.

Patients We assessed 92 hepatitis B cases and 98,069 controls from a population of 98,161 RA patients registered into the US Food and Drug Administration’s (FDA’s) adverse event database between 2004 and 2010.

Measurements A reporting odds ratio (ROR), a signal suggesting a risk for hepatitis B among antirheumatic agents, was measured.

Results Treatment with corticosteroids [ROR 2.3 (95 % confidence interval 1.3–4.0)], methotrexate [4.9 (3.9–6.0)], rituximab [7.2 (5.3–9.9)], tacrolimus [4.2 (1.5–11.9)], or reporting from Japan [2.2 (1.1–4.2)] were associated with higher signal, whereas adalimumab had a lower ROR [0.2 (0.1–0.4)].

Limitations There are known limitations of spontaneous reporting, such as underreporting, the Weber effect, reporting bias, indication bias, and limited clinical information such as HBV status.

Conclusions Adalimumab’s low reporting rate is most likely be due to notoriety. However, the possibility that adalimumab might suppress reactivation of HBV cannot be denied. Until the possibility is clarified in well-designed clinical studies, physicians should use adalimumab cautiously in patients with HBV.     

Subacute cutaneous lupus erythematosus,and positive anti-MDA5 antibody in clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease: A case report and literature review

BackgroundClinically amyopathic dermatomyositis (CADM) is a subtype of DM with characteristic cutaneous lesion with normal creatinine kinase levels. Presence of anti-melanoma differentiation-associated gene 5 (MDA5) antibody is found to be associated with rapidly progressive interstitial lung disease (RP-ILD). Aim of the work: to report a CADM patient with positive anti-MDA5 antibody and RP-ILD with clinical features of systemic lupus erythematosus (SLE) who clinically responded to a combination of cyclophosphamide and other conventional immunosuppressant. Case presentation: A 44-year-old Indian woman presented with classical cutaneous lesions of DM with normal creatinine kinase levels amongst other clinical features. She was initially diagnosed with SLE before developing RP-ILD and a positive MDA5 antibody. Anti-nuclear antibody, anti-dsDNA and anti-Sm antibody were negative. Serum ferritin level was very high (1599 ng/mL) as compared to C-reactive protein (23.4 mg/L). Anti-Ro-52 and anti-PM-Scl 75 were positive. High resolution computed tomography (HRCT) of the lungs revealed features consistent with ILD. Histology of her skin biopsy was consistent with subacute cutaneous lupus erythematosus (SCLE). Her diagnosis was revised to CADM with overlapping SCLE. She responded to a combination of hydroxychloroquine, cyclosporine-A, mycophenolate mofetil, pulse methylprednisolone and pulse cyclophosphamide 750 mg/month for 6 months. Her cutaneous lesions gradually improved with normalization of serum ferritin level. Repeated HRCT showed no further progression of the pulmonary fibrosis. Conclusion: CADM with positive anti-MDA5 antibody associated with RP-ILD is rare with a high mortality rate. Early recognition and prompt treatment with a combination of immuno-suppressant may improve the outcome of this complex disease.     

血清抗黑色素瘤分化相关基因抗体检测在多发性肌炎/皮肌炎患者中的意义

目的 检测多发性肌炎/皮肌炎(PM/DM)患者血清抗黑色素瘤分化相关基因(MDA5)抗体水平,探讨其在多发性肌炎/皮肌炎患者中的意义.方法 采用酶联免疫吸附试验(ELISA)法测定113例多发性肌炎/皮肌炎、30例系统性红斑狼疮(SLE),30例类风湿关节炎(RA),15例原发性干燥综合征(pSS),21例急性肺部感染患者以及50名健康对照组血清中抗MDA5抗体的阳性率.统计学方法采用t检验、Mann-Wittney U检验、X2检验、Fisher检验及Logistic多因素回归分析.结果 血清抗MDA5抗体的阳性率在多发性肌炎组、皮肌炎组、SLE组、RA组、SS组、肺部感染组及健康对照组分别是0、22.6％、3.3％、3.3％、0、0和0.皮肌炎组血清抗MDA5抗体阳性率(22.6％)明显高于多发性肌炎患者(0,P＜0.01),亦高于SLE患者(3.3％,X2=5.68,P＜0.05)、RA患者(3.3％,X2=5.68,P＜0.05)、pSS患者(0,P＜0.05)、肺部感染患者(0,P＜0.05)及健康对照(0,P＜0.01).皮肌炎亚组中,临床无肌病性皮肌炎(CADM)患者抗MDA5抗体阳性率(62.5％)较经典皮肌炎( CDM)患者高(18.4％,P＜0.05).抗MDA5抗体阳性的皮肌炎患者关节炎、发热、Ⅴ字疹、癌胚抗原升高、CA153升高的发生率及血清谷氨酰转肽酶(GGT)、铁蛋白浓度较抗MDA5抗体阴性患者显著升高(X2=4.08,8.06,6.357,32.4,4.867;Z=-2.86,-2.44;P均＜0.05);而抗核抗体阳性、血清肌酸激酶浓度及外周血T细胞、自然杀伤细胞计数则低于抗MDA5阴性组(X2=4.08;Z=-2.072,-2.013,-2.907;P均＜0.05).此外,抗MDA5抗体阳性的皮肌炎患者急性/亚急性间质性肺炎(A/SIP)的发生率(78.9％)显著高于阴性患者(3.2％)(P＜0.01).抗MDA5抗体诊断皮肌炎合并A/SIP的敏感性为88.2％,特异性为94％.多因素分析发现血清抗MDA5阳性为皮肌炎合并间质性肺疾病(ILD)患者死亡的独立危险因素(0R=8.46,95％CI 1.77～40.36,P＜0.01).结论 在我国多发性肌炎/皮肌炎患者人群,血清抗MDA5抗体主要存在于皮肌炎患者,是皮肌炎合并A/SIP的敏感及特异性血清学指标,也是皮肌炎合并ILD死亡的独立危险因素.     

Early diagnosis and treatment for remission of clinically amyopathic dermatomyositis complicated by rapid progress interstitial lung disease: a report of two cases

We report two cases of clinically amyopathic dermatomyositis (CADM) complicated by rapid progress interstitial lung disease (RPILD). The diagnosis of CADM was based on Gottron’s papule and RPILD, and the absence of muscle weakness. The female patients were treated with early immunosuppressive therapies including steroid pulse therapy, resulting in significant improvement in respiratory symptoms, clinical data, and imaging. Measurement of anti-CADM-140/MDA5 antibody was useful for obtaining a definitive diagnosis of CADM in these cases.     

Low positive titer of anti-melanoma differentiation-associated gene 5 antibody is not associated with a poor long-term outcome of interstitial lung disease in patients with dermatomyositis

Background

Anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5-Ab) is associated with fatal rapidly progressive interstitial lung disease (RP-ILD) in patients with dermatomyositis (DM). We attempted to clarify whether anti-MDA5-Ab is associated with long-term outcomes in patients with DM-ILD.

Flowcytometric analysis of bronchoalveolar lavage fluid cells in polymyositis/dermatomyositis with interstitial pneumonia

OBJECTIVE: Interstitial lung disease (ILD) is a complication occurring in 10-30% of patients with polymyositis/dermatomyositis (PM/DM) as well as in those with progressive systemic sclerosis (PSS). Clinical features are different between these two disease states, notably with respect to the duration of manifestations, pathological findings, response to steroid therapy etc. However, dissimilarities in pulmonary inflammatory cell characteristics, which, if present at all, would be of critical importance, remain as yet to be clarified. METHODOLOGY: The phenotypes of lymphocytes and alveolar macrophages in bronchoalveolar lavage fluid (BALF) were analysed to elucidate phenotypic peculiarity of pulmonary inflammatory cells of ILD in PM/DM. Eight PM/DM patients with ILD (mean age 47.9 years) were examined by bronchofibrescopy under local anaesthesia. Bronchoalveolar lavage was performed from the right middle lobe using four 50 mL aliquots of normal saline and the recovered fluid was compared with BALF of ILD in PSS. RESULTS: Bronchoalveolar lavage fluid cells of PM/DM patients with ILD showed an increased percentage of CD8+ lymphocytes, in particular CD8+ histocompatibility leucocyte antigen-DR positive lymphocytes and CD8+ CD11b-lymphocytes, both of which represent cytotoxic T cells. However, phenotypic differences in these lymphocytes were not found between PM and DM. The percentage of alveolar macrophages with expression of histocompatibility leucocyte antigen-DQ was significantly different among the three groups (PM/DM, PSS, healthy volunteers). CONCLUSIONS: Cytotoxic T cells may be major pulmonary inflammatory cells of ILD in PM/DM with no apparent difference between PM and DM. In contrast, ILD in PSS was suggested as being likely to be characterized by activated macrophage.     

Two cases with autoantibodies to small ubiquitin‐like modifier activating enzyme: A potential unique subset of dermatomyositis‐associated interstitial lung disease

The presence of anti‐aminoacyl tRNA synthetase (ARS) or anti‐melanoma differential‐associated gene 5 (MDA5) is strongly related to interstitial lung disease (ILD) in patients with dermatomyositis (DM). Several studies suggest a potential relationship between ILD and anti‐small ubiquitin‐like modifier activating enzyme (SAE) antibody in DM patients, but detailed clinical characteristics of anti‐SAE‐associated ILD still remain unknown. We have experienced 2 cases who were positive for anti‐SAE antibody, who presented with ILD in the context of clinically amyopathic DM. These 2 patients had the following common ILD characteristics: an insidious course with preserved pulmonary function; a limited extent of pulmonary lesions with subpleural peripheral‐dominant small ground glass opacity/consolidation on high‐resolution computed tomography; and a favorable treatment response. These findings suggest that anti‐SAE‐associated ILD is unique in terms of clinical and imaging features and differs from ILD associated with anti‐ARS or anti‐MDA5 antibody.