Received date: October 27, 2016; Accepted date: December 02, 2016; Published date: December 05, 2016
Citation: Liao X, Liu Y, Sun Y, Chen S, Shi G (2016) Serological Biomarkers of Dermatomyositis – Associated Interstitial Lung Disease. J Pulm Respir Med 6:383.doi: 10.4172/2161-105X.1000383
Copyright: © 2016 Liao X, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Dermatomyositis (DM) is a subset of idiopathic inflammatory myopathies (IIM) which is characterized by chronic inflammation of skin and muscle weakness, and often involving other organs, such as skin, heart, gastrointestinal tract, pulmonary, and joints. Interstitial lung disease (ILD) is the most common internal organ manifestation that affects the prognosis of DM patients. The mortality is very high in DM-ILD patients especially in those with rapid ILD due to the lack of effective treatment. An early diagnosis of ILD in DM patients is critical important. In recent years, many studies focused on detecting serological biomarkers that can be used in prediction and evaluation of DM-ILD. Here we reviewed recent studies about serological biomarkers of DM-ILD. An overview of those biomarkers may help us have a better management of DM-ILD and may give us a better understanding about the pathogenesis of DM-ILD.
Dermatomyositis; Interstitial lung disease; Biomarkers
Dermatomyositis (DM) is a subset of idiopathic inflammatory myopathies (IIM) which is characterized by chronic inflammation of skin and muscle weakness, and often involving other organs, such as skin, heart, gastrointestinal tract, pulmonary, and joints [1-5]. The subtypes of DM include classical DM, which has muscle manifestations as well as a variety of cutaneous manifestations; another subset of DM is called clinically amyopathic dermatomyositis (CADM), referring to the typical clinical manifestations of dermatomyositis skin and few have the clinical manifestations of muscle weakness [6,7].
Interstitial lung disease (ILD) is the most common internal organ manifestation that affects the prognosis of DM patients . It has been estimated that about 35% to 40% of patients with DM can incur interstitial lung disease (ILD) [4,9]. In the recent researches, the prevalence of ILD in myositis (include PM and DM) has reached close to 50%, ranging from 21% to 78% [8,10-16]. There are two different subtypes of ILD in DM viz., chronic/subacute interstitial lung disease, and rapid progressive interstitial lung disease (RP-ILD) [8,10]. RPILD is critical important in the clinical management of DM patients since the mortality is very high and prognosis is very poor , with a 6-month survival rate of 40.8% to 45.0% [14,17]. Certain studies report that CADM patients, particularly in those Japanese descent, often suffer rapidly progressive interstitial lung disease . Compared with classic DM with ILD, CADM-associated ILD often enjoys a worse prognosis [18-21].
The pathogenesis of ILD is not completely clear yet and lack of effective treatment. An early diagnosis of ILD, especially RP-ILD is quite important for the management of DM-ILD patients. Serological biomarkers are widely used in diagnosis of many kinds of diseases. In recent years, many researches focused on screening new biomarker specific for DM-ILD found several serological biomarkers might be used in clinical management of DM-ILD patients. Study of these new biomarkers can help us know more about the pathogenesis, pathological process and prognosis of the disease. In this article, we reviewed recent reports of biomarkers associated with ILD in DM patients.
Anti-aminoacyl-transfer RNA synthetase antibodies
There is evidence that DM is an autoimmune disease. Approximately 50% to 70% of patients have been detected with circulating myositisspecific autoantibodies (MSAs). The primary component of MSAs is anti-synthetase antibodies. Numerous clinical cases suggest that in patients with anti-aminoacyl-transfer RNA synthetase antibodies (anti- ARS Abs), known as anti-synthetase antibodies, more than 63% to 75% will appear ILD [22,23], yet, the relationship between anti-ARS Abs and activity of dermatomyositis or ILD is disputable .
Thus far, there are eight different anti-ARS antibodies have been identified: anti-Jo-1 (histidyl), anti-PL-7 (threonyl), anti-PL-12 (alanyl), anti-EJ (glycyl), anti-OJ (isoleucyl), anti-KS (asparaginyl), anti-Zo (phenylalanyl), and anti-tyrosyl-tRNA synthetase antibodies [25-32]. There are some differences in detail clinical manifestations among patients with different anti-ARS antibodies. Anti-Jo-1 antibody, some studies have shown that patients with this antibody (a major type of anti-ARS antibodies) positivity combined ILD, meanwhile with high prevalence of myositis, and its prognosis is better than others [6,33]. However, anti-OJ, anti-PL-12, and anti-KS are more likely associations with ILD than myositis, particularly anti-KS . Anti-PL-7 may be associated with DM-scleroderma overlap syndrome as well as with ILD, especially in Japanese patients . It is still uncertain whether these autoantibodies play a role in the pathophysiologic mechanisms of disease.
In a retrospective study, Yoshifuji et al.  has shown that patients with ILD had a better response to the initial stage of cortisol therapy, but the recurrence rate was significantly increased compared with those who were negative for the anti-ARS antibodies. In addition, anti-ARS antibodies frequently appear in sera laboratory testing from chronic/subacute ILD patients and these patients tend to have recurrent illness. Early anti-ARS antibody screening can be used to predict lateonset DM, if the patient had pulmonary involvement as the initial manifestation of the disease, and can predict the progression of ILD in patients with dermatomyositis. However, certain literatures report that although these antibodies have myositis-specific, they appear less frequently in DM patients , and the role of these antibodies in the pathogenesis of DM patients combined with ILD is yet to be further studied.
Approximately 20% to 30% of the DM patients may be detected to have anti-Mi-2, which interacts with Mi-2, a nuclear helicase protein. It is the primary DM-specific MSA to be identified. The data shows that the DM patients with anti-Mi-2 positive are more likely to have lower morbidity of ILD and malignancy, as well as sensitivity to steroids .
Recently, some Japanese literature reveals, the discovery of a novel antibody in CADM patients, the anti-MDA-5/CADM-140 antibody . Since the Japanese scientists found that this antibody directly interacts with an RNA helicase encoded by melanoma differentiationassociated gene 5 (MDA-5), this antibody is also referred to as anti- MDA5 antibody . This RNA helicase defense the virus infection in the innate immune. CADM patients who have this antibody appear are associated with an obviously higher rate of rapidly progressive ILD, and a severe clinical course [18-21,39]. Serological laboratory testing of approximately a quarter of patients with DM or a half of patients with CADM may presence this antibody, whereas it cannot be detected in other disease [18,39-42]. Currently, the presence of this antibody has been detected in an increasing number of races, including Caucasian, Israel, and so on [42,43].
Chronic and subacute ILD patients often represent anti-synthetasepositive, whereas acute ILD patients are often associated with anti- MDA5 antibody. In the presence of anti-synthetase antibodies, approximately 30% to 50% of patients initially showed lung lesions [22,35,44].
There are also some DM specific MSA, but they need further analysis. These antibodies include anti-SAE, a novel autoantibody directed against small ubiquitin-like modifier activating enzyme, only in a UK cohort of DM patients. Betteridge et al.  have also found that the DM patients with this autoantibody be likely to have a lower prevalence of ILD.
There are other autoantibodies, which are not only present in myositis, but also occur in other connective tissue diseases, particularly in patients with systemic scleroderma and overlap syndrome. Anti- SS-A/Ro antibody, coexistence of anti-SS-A and anti-Jo-1 antibody, recently certain studies finding that may be a biomarker in DM-ILD patients. Compared with the anti-SS-A/Ro antibody-negative patients, anti-SS-A/Ro antibody present in anti-synthetase syndrome patients may be accompanied seem more severe ILD, and a poor response immunosuppressive treatment. Meanwhile, compared with classical dermatomyositis without anti-synthetase syndrome, the patients with anti-synthetase syndrome showed elevate frequency of the presence of ILD, and anti-Ro/SSA antibodies [46,47]. Muro et al.  has report that they found a novel autoantibody. In their study, 126 DM patients, of whom 3 patients had anti-PM/Scl antibodies, and the 3 patients were all complicated with ILD. The clinical manifestations of ILD for these three patients did not have a fatal outcome . Principal autoantibodies associated with ILD in DM patients are summarized in Table 1.
|Autoantibody||Prevalence in DM patients with ILD (%)||Prevalence in DM patients without ILD (%)||Clinical significance||References|
|Anti-ARS autoantibodies||>63% to 70.4%||3%||Associated with chronic or recurrent ILD.||[22,47]|
|13.6%||24%||Prevalence of ILD is lower in anti-Jo-1 positive DM patients than other anti-ARS autoantibodies-positive DM patients.||[6,31,33]|
|undetermined||undetermined||Patients with positive anti-Mi-2 often have lower morbidity caused by ILD and sensitivity to steroids.|||
|Anti-MDA5autoantibody||92%-100%||63.3%||Specific to CADM; often associated with rapidly progressive ILD, severe skin manifestations; The levels of this antibody would be helpful in predicting the course of ILD and facilitating better therapeutic targeting.||[18,20,39-42]|
|Anti-SAE autoantibody||Maybe Lower||undetermined||More research is needed on this antibody.|||
|undetermined||undetermined||Patients with this antibody often have a good response of oral prednisolone and immune suppressiveagent therapy.|||
Table 1: Principal autoantibodies associated with ILD in DM patients.
However, so far, there is no conclusive evidence shown that these autoantibodies are also associated with other phenotype of ILD, such as nonspecific interstitial pneumonitis (NSIP).
Although HRCT examination of pulmonary is the most sensitive method for detection and prediction of ILD activation as of now. However, frequent exposure to CT high-radiation is harmful to the human body. Therefore, it is important to detect the biomarkers that may accompanying with inflammatory activation of lung.
Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) are recently identified biomarkers associated with DM-ILD. They are both secreted by type II alveolar epithelial cells. Some studies have shown that they are significantly elevated in the serum of patients with DM-ILD, and they are positively correlated with the prognosis of the disease [49-52]. They can be used as biomarkers in the serum of DM-ILD patients. Ohnishi , also suggested that KL-6 might be more sensitive than SP-D in the detection of DM-ILD patients [53,54]. Some studies have indicated that in a more common type of disease in ILD, idiopathic pulmonary fibrosis (IPF) also known as usual interstitial pneumonia (UIP), the level of KL-6 and SP-D is also higher than the normal group, and the increased levels predictors of worse survival [55-58]. However, so far, there is no conclusive evidence shown that KL-6 and SP-D are also associated with other phenotype of idiopathic interstitial pneumonia (IIP), such as nonspecific interstitial pneumonitis (NSIP). Clinical significance of lung epithelium specific biomarkers is summarized in Table 2.
|Lung epithelium-specific biomarkers||Serum level in DM patients with ILD||Serum level in DM patients without ILD||Clinical significance||References|
|KL-6||Median 995 (range 533-2318) U /mL||Median 322 (range 132-1225) U/mL||May be the best serum marker for ILD; Reflected the extent and severity of ILD; The level of KL-6 >1000 U/ mL may indicate poor prognosis; The changes in serum KL-6 levels correlated significantly with changes in pulmonary function tests. The level of KL-6 also associated with UIP.||[50,51,53]|
|SP-D||118.7ng/ml± 220.2 ng/ml||38.7ng/ml± 21.0 ng/ml||The serum SP-D level in PM/DM patients with ILD was significantly elevated compared with those without ILD, it can reflect the severity of ILD in patients with PM/DM. The level of SP-D also associated with UIP.|||
Table 2: Principal lung epithelium-specific biomarkers associated with ILD in DM patients.
In a number of studies on juvenile dermatomyositis (JDM), accompanied with rapidly progressive interstitial lung disease (RPILD) group and chronic ILD (C-ILD) group, the serum B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) titers were significantly higher, while the C-ILD group was significantly higher than healthy controls. They also indicated that the levels of BAFF and APRIL were associated with serum Krebs von den Lungen-6 (KL-6) and interleukin 18 (IL-18) in patients with ILD, and the patients have high titer anti-MDA5 (>200 U), also had higher levels of BAFF and APRIL . However, in the adult DM-ILD, whether there is a correlationship between titer of these cytokines and RP-ILD, there is no report so far.
Cathepsin B (CB) is a cysteine protease, which belongs to the family of the papaya protease, mostly located in lysosomes . The function of this protease is mainly involved in the turnover of proteins and play a various roles in maintaining the normal metabolism of cells. Recent year, Zhang et al.  have showed that in cytoplasm of the lung tissues from PM/DM patients, the number of CB-positive cells was obviously higher than healthy controls. They also suggest that CB through activate the TNF-a signaling mediates pulmonary cell apoptosis.
Some research suggests that in the serological detection of DM patients, IL-18 was significantly elevated, especially with disease activity and ILD presence in DM. At the same time, Gono et al.  also found in some patients with the activity of acute ILD in DM, their serum ferritin and IL-18 both higher than others.
There are many cytokines and chemokines could take part in the whole disease status, including dermatitis and ILD, in DM . The levels of IL-6, IL-8, IL-10, TNF-a and IP-10 (IFN-g-inducible 10 kDa protein) were significantly elevated in the DM/PM/CADM patients with ILD [62-64]. And, the most significantly cytokine was TNF-a . In addition, the titer of serum IL-8 between chronic ILD (anti- ARS-ILD) and RP-ILD (anti-MDA5-ILD) were different, the levels were significantly higher in RP-ILD than chronic ILD . Thus, the levels of IL-8 can be a useful predictor for fatal outcomes due to ILD with PM/DM. While some studies have reported that IL-6, IL-8, and IL-10 may be significant contributors to up-regulation of the level of ferritin in PM/DM, thus induce RP-ILD, there are some reports found IFN-g-inducible chemokines C-X-C motif ligand 9 (CXCL9) and CXCL10 were associated with anti-Jo-1 antibody-associated ILD [64,65]. In these cytokines, IL-6 and IL-8 also associated with IPF, and high concentrations may associate with worse survival . Cytokines involved in DM-ILD are summarized in Table 3.
|BAFF||Serum BAFF titers were significantly higher in the juvenile dermatomyositis (JDM) patients with RP-ILD versus those with C-ILD and healthy controls.|||
|APRIL||Serum APRIL titers were significantly higher in the juvenile dermatomyositis (JDM) patients with RP-ILD versus those with C-ILD and healthy controls.|||
|CB||The cytokine may act through activate the TNF-a signaling and mediate pulmonary cell apoptosis.|||
|IL-6||IL-6 was associated with global disease activity in PM, DM and CADM; The cytokine level was high, especially in ILD with PM/DM; IL-6 is significant factors that contribute to serum ferritin levels. The level of IL-6 also associated with UIP.||[58,61]|
|IL-8||Serum IL-8 levels may contribute to the differences in pathophysiology between chronic ILD (anti-ARS-ILD) and RP-ILD (anti-MDA5-ILD); A useful predictor for fatal outcomes due to ILD with PM/DM. The level of IL-8 also associated with UIP.||[58,61]|
|IL-10||IL-10 was associated with global disease activity in PM, DM and CADM; a significant factor that contribute to serum ferritin levels.||[58,61]|
|IL-18||IL-18 was significantly elevated, especially associated with disease activity and ILD presence in DM|||
|IP-10||IP-10 was associated with global disease activity in PM, DM and CADM; The cytokine level was high, especially in ILD with PM/DM.|||
|TNF-α,||In IL-6, IL-8, IL-10 and TNF-a, TNF-αmay be the cytokine that was most significantly associated with ILD in PM/DM/CADM.|||
|CXCL9||The level was associated with anti-Jo-1 antibody-associated ILD.|||
|CXCL10||The level was associated with anti-Jo-1 antibody-associated ILD.|||
Table 3: Principal cytokines associated with ILD in DM patients.
Other serological biomarkers
Serum ferritin is another novel biomarker detected in DM-ILD patients. They may be found mainly in patients with acute or subacute progressive ILD, particularly in CADM patients [41,67-69]. In addition, the studies have shown that the level of serum ferritin was obviously higher in ILD patients with anti-MDA5-positive [68,69].
Some serum protein biomarker, such as the general inflammatory markers C-reactive protein (CRP) have been reported that may associated with anti-Jo-1 antibody-associated ILD .
Limited articles reported BALF cells profiles. There were two different studies suggested that patients with ILD had a poor outcome when the initial BALF showed neutrophilic alveolitis [8,10]. However, these markers weather have universality in the serological detection of patients with dermatomyositis-associated ILD, are in need of more researches.
There are some new biomarkers which have been reported or accepted so far associated with DM, include anti-MJ/nuclear matrix protein 2 (NXP-2) and anti-small ubiquitin-like modifier-1 (SUMO- 1) activating enzyme (SAE), but whether they also play a role in the pathogenesis of DM patients with ILD, also needs more research. Other serological biomarkers of DM-ILD are summarized in Table 4.
|Ferritin||Serum ferritin can be useful as a predictor of the occurrence of acute or subacute progressive ILD (A/SIP) and correlates with the prognosis of A/SIP in DM; The cumulative survival rate was significantly lower when the ferritin levels > or =1500 ng/ml.|||
|CRP||The level is associated with anti-Jo-1 antibody-associated ILD.|||
|BALF cells profiles||Two different studies suggested that patients with ILD had a poor outcome when the initial BALF showed neutrophilic alveolitis.|||
Table 4: Other biomarkers associated with ILD in DM patients.
ILD is the most frequent complication of DM patients [23,70], and the morbidity and mortality will be greatly increased in DM-ILD patients [12,23]. Fujisawa et al.  indicate that although another idiopathic inflammatory myopathies (IIM), known as polymyositis (PM), appeared to have a similar frequency of ILD as DM patients, however, the mortality of PM-ILD is lower, and more sensitive to drug treatment, and the prognosis is better than DM-ILD [71-73]. Early diagnosis of ILD is critical important for the management of DM patients since there is still lack of effective treatment of DM-ILD. Serological biomarkers are the most frequent method used in diseased diagnosis. Besides other testing methods include high-resolution CT (HRCT) scanning and pulmonary function tests for DM-ILD patients, serological biomarkers are also needed.
Studies in recent years have found several serological biomarkers associated with DM-ILD. Autoantibodies including anti-aminoacyltransfer RNA synthetase antibodies (except anti-Jo-1) and anti- CADM-140 may be associated with high prevalence of ILD in DM patients. Lung epithelium-specific biomarkers including Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) are newly detected biomarkers that have great potential in clinical management of DM-ILD. Cytokines including B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), cathepsin B, IL-6, IL-8, IL-10, IL-18, IP-10, TNF-α, CXCL9 and CXCL10 are increased in DM-ILD patients and may be involved in the pathogenesis of DM-ILD. Other serological biomarkers such as CRP and ferritin were also increased in DM-ILD patients.
Despite the growing number of biomarkers have been detected, there are still some limitations in these studies. First of all, studies on these biomarkers are mostly retrospective analyses, and due to the low incidence of DM-ILD, the number of patients in these reports was always relatively small. We need further prospective studies in larger number of DM-ILD patients, such as anti-ARS autoantibodies, anti- Jo-1 autoantibody, anti-Mi-2 autoantibody, anti-SAE autoantibody, anti-PM/Scl autoantibodies. Secondly, although some biomarkers have been confirmed by a large number of experiments, even has been used for clinical diagnosis, like anti-MDA5 autoantibody, KL-6, IL-6 and IL- 8, we still know very little about the function of these biomarkers so far, more researches on their function may help us know the pathogenesis of DM-ILD. There are some newly detected biomarkers associated with autoimmune associated ILD, for instance, matrix metallo-proteinase-7 (MMP-7) is a potential biomarkers for rheumatoid arthritis-interstitial lung disease (RA-ILD). Whether there is clinical significance of these biomarkers in the serum of DM-ILD patients, may be a new research direction in the future. As more and more new biomarkers are detected, we will know more about the pathogenesis, pathological process, prognosis of the DM-ILD, and may provide us new treatment target for DM-ILD.
A large number of novel biomarkers have been found associated with DM-ILD, some may be used for diagnosis, evaluation of disease severity, progression and responsiveness to treatments. Clinical significance of biomarkers in DM-ILD patients including anti-MDA5 autoantibody, KL-6, SP-D, IL-6 and IL-8 have been proved by a large number of experiments, and KL-6 have been used in clinical management of DM-ILD as well as other type of ILD. Other biomarkers, like anti-ARS autoantibodies, anti-Jo-1 autoantibody, anti-Mi-2 autoantibody, anti- SAE autoantibody, anti-PM/Scl autoantibodies, BAFF, APRIL, CB, IL- 10, IL-18, IP-10, TNF-α, CXCL9, CXCL10, ferritin, CRP, BALF cells profiles and MMP-7, may be used as potential serological biomarker in DM-ILD management, however, their clinical significance still need to be further evaluated in prospective studies with larger number of DM-ILD patients. Other kind of biomarkers including KL-6, SP-D, IL-6 and IL-8 have been proved not only associated with DM-ILD, but also with IPF.
The work was partially supported by NSFC (Natural Science Foundation of China) grant 81273285 and Xiamen Science and Technology Bureau Project no.3502Z20144005 to Dr. Guixiu Shi and NSFC (Natural Science Foundation of China) grant 81501407 to Dr. Yuan Liu.
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