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Clinical and HRCT features of amyopathic dermatomyositis associated with interstitial lung disease: A retrospective study of 128 patients with connective tissue disease-related interstitial lung disease
Corresponding author. Qunli Ding, Department of Respiratory, The Affiliated Hospital of Medical School of Ningbo University Jiangbei District, Ningbo City People's Road No. 247, Ningbo, Zhejiang, China.
This study retrospectively analyzed the laboratory data and chest images of patients with amyopathic dermatomyositis associated with interstitial lung disease (ADM-ILD) and patients with other connective tissue disease-related ILDs (CTD-ILDs) to find a characteristic index for the early recognition of ADM-ILD and help clinicians consider the possibility of ADM-ILD as soon as possible.
Methods
In our cohort study, the records of 128 Chinese patients with CTD-ILD, including 33 ADM-ILD patients, 37 rheumatoid arthritis (RA)-ILD patients, 33 primary Sjogren's syndrome (pSS)-ILD patients, 14 systemic sclerosis (SSc)-ILD patients and 11 systemic lupus erythematosus (SLE)-ILD patients. The patients’ clinical features, laboratory parameters, and chest HRCT findings were analyzed.
Results
ADM-ILD patients generally had significantly higher LDH (333.52±160.21 U/L), AST (66.21±83.66 U/L), and CK-MB (18.23±8.28 U/L) levels than other CTD-ILD patients. A total of 90.91% (30/33) of ADM-ILD patients had elevated LDH. Patients with ADM-ILD were more prone to organizing pneumonia radiologic patterns on chest HRCT scans than patients with other CTD-ILDs (=37.39, p < 0.001) and were found in 18 of 33 ADM-ILD patients. Anti-MDA5 (45.45%) was the most commonly detected autoantibody in ADM-ILD patients, followed by anti-PL-7 (21.21%), anti-Jo-1 (12.12%), and anti-PL-12 (9.09%), and levels of ALT (96.93±119.79 vs. 17.50±6.218 U/L), AST (113.00±106.13 vs. 23.56±6.91 U/L), LDH (415.00±198.51 vs. 261.94±67.75 U/L) and CK-MB (22.57±5.91 vs. 14.61±8.36 U/L) were significantly higher in anti-MDA5-positive patients, but these patients had significantly lower WBC counts (4.82±2.61 vs. 7.14±3.00 × 109/L), lymphocyte counts (0.72±0.20 vs. 1.23±0.53 × 109/L), and ALB levels (31.90±4.76 vs. 35.49±4.71 g/L).
Conclusions
ADM-ILD patients have higher serum LDH, AST and CK-MB levels, especially serum LDH levels, and are more prone to organizing pneumonia radiologic patterns on chest HRCT scans than other CTD-ILD patients. A high level of serum LDH with ILD may be a useful characteristic index for recognizing ADM-ILD.
Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases characterized by inflammation of the skeletal muscles. The most common subgroups in adults are dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM).
The clinical manifestations of IIM are diverse and are characterized by various degrees of muscle, skin, and lung involvement. Interstitial lung disease (ILD) is a common complication of IIMs that results in high mortality, with an estimated prevalence of 30%.
With the widespread awareness of myositis-specific autoantibodies (MSAs) and the myositis-associated autoantibody (MAA) spectrum, an increasing number of amyopathic dermatomyositis (ADM) cases have been diagnosed, especially with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. ADM is defined as a subset of DM characterized by typical cutaneous manifestations of classic DM lasting 6 months or longer with no clinical evidence of muscular manifestations and no elevation in serum creatine kinase (CK).
Would a new name hasten the acceptance of amyopathic dermatomyositis (dermatomyositis sine myositis) as a distinctive subset within the idiopathic inflammatory dermatomyopathies spectrum of clinical illness?.
There is a strong correlation between the incidence of ILD in IIM patients and myositis-specific autoantibodies. The incidence of ILD in MDA5-positive ADM patients is more than 90%,
and ADM-ILD with MDA5 positivity is characterized by a risk of rapidly progressive ILD (RP-ILD), which has an estimated prevalence of 26.8–62.5%, especially in East Asia,
Differential clinical features of patients with clinically amyopathic dermatomyositis who have circulating anti-MDA5 autoantibodies with or without myositis-associated autoantibodies.
Anti-melanoma differentiation-associated gene 5 is associated with rapidly progressive lung disease and poor survival in US Patients with amyopathic and myopathic dermatomyositis.
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.
and is often resistant to intensive therapy, such as high-dose corticosteroids combined with cyclosporine A (CsA), tacrolimus, or cyclophosphamide agents. The result is acute fatal respiratory failure, and the 6-month mortality rate is as high as 45.0–64.3%.
Clinical effects of direct hemoperfusion using a polymyxin B-immobilized fiber column in clinically amyopathic dermatomyositis-associated rapidly progressive interstitial pneumonias.
Previous studies showed that patients who were treated intensively with combination immunosuppressive therapy upon diagnosis with ADM-ILD had better survival outcomes than those who received immunosuppressive therapy using a sequential approach after failure of the initial treatment.
Early intervention with corticosteroids and cyclosporin A and 2-hour postdose blood concentration monitoring improves the prognosis of acute/subacute interstitial pneumonia in dermatomyositis.
Therefore, early diagnoses and timely treatment are very important for reducing the mortality of ADM-ILD.
However, ADM diagnosis has embraced the use of overlapping syndromes to account for clinical heterogeneity and the lack of muscular manifestations and elevated CK, making the diagnosis even more difficult. This study retrospectively analyzed the laboratory data and chest images of 128 patients with CTD-ILD, including 33 ADM-ILD patients, to establish a characteristic index for the early recognition of ADM-ILD and alert clinicians to the possibility of ADM-ILD as early as possible.
Methods
Ethics approval and consent to participate
Written informed consent was obtained from all participants. The cohort study was approved by the institutional review board of the affiliated hospital of medical school of Ningbo university, Ningbo, China. (IRB no:KY20210905). Written informed consent from study subjects was waived because of the retrospective design.
Subjects
We retrospectively reviewed the medical records of patients who were diagnosed with ILD, including idiopathic pulmonary fibrosis (IPF), idiopathic interstitial pneumonia (IIP), connective tissue disease (CTD)-associated ILD, interstitial pneumonia with autoimmune features (IPAF), fibrotic hypersensitivity pneumonitis (HP), and ILDs related to occupational exposures, between January 2017 and November 2021 at the Affiliated Hospital of Medical School of Ningbo University. 150 patients diagnosed with CTD-ILD were screened (Fig. 1). The CTDs included were amyopathic dermatomyositis (ADM), rheumatoid arthritis (RA), primary Sjogren's syndrome (pSS), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). PM/DM with elevated CK and/or muscular manifestations were not included. The diagnosis of a specific CTD was based on validated classification criteria. ADM was diagnosed according to the Sontheimer criteria.
Would a new name hasten the acceptance of amyopathic dermatomyositis (dermatomyositis sine myositis) as a distinctive subset within the idiopathic inflammatory dermatomyopathies spectrum of clinical illness?.
The exclusion criteria were as follows: (1) patients with malignancy at the beginning of diagnosis (n = 4); (2) patients who met ≥2 CTD classification criteria (n = 7); (3) patients with a history of taking drugs that can cause hallmark cutaneous manifestations of CTD (n = 2); and (4) patients treated with systemic glucocorticoid and/or immunosuppressive therapy before the diagnosis of CTD-ILD (n = 7). In addition, 18 cases of ADM-ILD were provided by Ningbo First Hospital from January 2018 to November 2021. Finally, 128 patients (including 33 ADM-ILD patients, 37 RA-ILD patients, 33 pSS-ILD patients, 14 SSc-ILD patients and 11 SLE-ILD patients) were included in this study (Fig. 1).
Data collection
Clinical data, including detailed patient histories, clinical manifestations, laboratory results and chest HRCT images, were obtained from the medical records at the time of CTD-ILD diagnosis.
Clinical manifestations included (1) symptoms related to CTD, such as arthralgia, fever, rash, and Raynaud's phenomenon, and (2) symptoms related to ILD, such as dry cough, shortness of breath, exertional dyspnea, clubbed fingers, and crackles.
Laboratory parameters, including the white blood cell count, C-reactive protein, erythrocyte sedimentation rate, albumin, alanine aminotransferase, aspartate aminotransferase, creatine kinase, lactate dehydrogenase, immunoglobulin, antinuclear antibodies, anti-Jo-1 antibodies, myositis-specific antibodies, myositis-associated antibodies, etc., were tested in these patients upon enrollment.
HRCT findings
HRCT examinations of the lung were performed in 1.0 or 1.5 mm-thick sections to evaluate radiographic abnormalities. Independent, separate, retrospective reviews of the chest HRCT images of each patient were performed by two radiologists. The ILD patterns were classified according to the criteria of the 2013 ATS/ERS classification of idiopathic interstitial pneumonias (IIPs)
An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
as follows: definite or probable usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), lymphoid interstitial pneumonia (LIP), organizing pneumonia (OP), and mixed patterns. The diagnosis of ILD radiologic pattern relied on consensus opinion from two radiologists.
Statistical analysis
Continuous variables are expressed as the mean ± SD. The differences in clinical and laboratory data among CTD-ILD patients were analyzed by single-factor variance, and Dunnett's t test was adopted for multiple comparisons. For two-group comparisons of the binary data, either the chi-squared test or Fisher's exact test was used, t test was used in comparison of continuous data, and categorical data are expressed as positive “+” or negative “-”. Statistical analyses were performed using GraphPad Prism 9 software and SPSS 24.0 statistical software. A p value < 0.05 was considered statistically significant.
Results
Comparisons of clinical and laboratory data among ADM-ILD, RA-ILD, pSS-ILD, SSc-ILD and SLE-ILD patients
For all included patients, age, sex, clinical features, and laboratory data are summarized in Table 1. There were statistically significant differences in the white blood cell (WBC), platelet, lymphocyte, erythrocyte sedimentation rate (ESR), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase-MB (CK-MB) and IgG. Furthermore, through multiple comparisons between ADM-ILD and other types of CTD-ILD, we found that ADM-ILD patients generally had higher AST, LDH and CK-MB levels than other CTD-ILD patients, and the difference was statistically significant (Fig. 2); 42.42% (14/33), 90.91% (30/33) and 27.27% (9/33) of ADM-ILD patients had elevated AST, LDH and CK-MB levels, respectively. We also evaluated multiple comparisons between patients with other types of CTD-ILDs and ADM-ILD patients with or without anti-MDA5 positivity. ADM-ILD patients with or without anti-MDA5 positivity had significantly higher LDH levels than other CTD-ILD patients (Supplement 1). However, there were no significant differences in their levels of AST and CK-MB.
TABLE 1Comparison of clinical data and laboratory findings among ADM-ILD, RA-ILD, pSS-ILD, SSc-ILD and SLE-ILD.
Figure 2ADM-ILD patients had significantly higher AST (A), LDH (B), and CK-MB (C) levels than other CTD-ILD patients. Abbreviations described in Figure 1. *: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001.
The ILD radiological patterns of patients with ADM-ILD and other CTD-ILD are shown in Table 2. We divided them into the ADM-ILD group (n = 33) and the other CTD-ILD group (n = 95). Patients with ADM-ILD were more prone to OP radiologic patterns on chest HRCT scans than patients with other CTD-ILDs, and the difference was statistically significant (=37.39, p < 0.001). However, there was no difference between the ADM-ILD and other CTD-ILD groups in NSIP radiologic patterns (=2.99, p = 0.084).
TABLE 2ILD radiologic patterns among ADM-ILD, RA-ILD, pSS-ILD, SSc-ILD and SLE-ILD.
Demographic, skin manifestation, laboratory parameter, antinuclear antibody and ILD radiologic pattern data are shown in Table 3. The mean age at ADM-ILD diagnosis was 57.67 ± 14.63 years, and the ratio of females to males was 2.67:1. Common clinical manifestations included dyspnea (54.55%), cough (48.48%), fever (30.30%) and arthralgia (30.30%). Gottron's sign (57.58%) and heliotrope rash (48.48%) were common in those patients, especially in anti-MDA5-positive patients. High levels of ESR, LDH, ALT, AST, and immunoglobulin G (IgG) were common in ADM-ILD patients, while the levels of serum albumin (ALB) and lymphocyte count were lower than normal values. CK, CK-MB and high sensitivity C-reactive protein (hsCRP) were always in the normal reference range. The detection of myositis autoantibodies in ADM-ILD patients are shown in Table 4. In the detection of MSAs in our study, anti-MDA5 was the most commonly detected autoantibody (45.45%). Anti-aminoacyl-tRNA synthetase antibodies (anti-ARS) were relatively less common in ADM-ILD. The positive rate of anti-PL-7 was 21.21%, followed by anti-Jo-1 (12.12%), anti-PL-12 (9.09%), anti-EJ (9.09%) and anti-OJ (3.03%). Anti-Ro-52 had the highest positivity rate (52.4%) among the MAAs. Other MAAs, such as anti-PM-Scl100 (3.03%) and anti-PM-Scl75 (3.03%), were less frequent in ADM-ILD.
TABLE 3Clinical data, laboratory data, and ILD radiologic patterns in all patients, anti-MDA5-positive patients, and anti-MDA5-negative patients.
When compared to ADM-ILD with anti-MDA5-positive patients and anti-MDA5-negative patients, anti-MDA5-positive patients tended to have a younger onset age (with a mean age of 49.80±14.37 years); levels of ALT (96.93±119.79 vs. 17.50±6.218 U/L), AST (113.00±106.13 vs. 23.56±6.91 U/L), LDH (415.00±198.51 vs. 261.94±67.75 U/L) and CK-MB (22.57±5.91 vs. 14.61±8.36 U/L) were significantly higher in anti-MDA5-positive patients; and levels of WBC (4.82±2.61 vs. 7.14±3.00 × 109/L), lymphocyte count (0.72±0.20 vs. 1.23±0.53 × 109/L), platelet count (200.40±66.83 vs. 239.56±38.47 × 109/L), and ALB (31.90±4.76 vs. 35.49±4.71 g/L) were significantly lower in anti-MDA5-positive patients.
Discussion
In the present study, we retrospectively reviewed 128 cases of CTD-ILD, including 33 ADM-ILD patients, and assessed their clinical features. Our findings demonstrated that ADM-ILD patients generally had higher AST, LDH and CK-MB levels than other CTD-ILD patients, and 90.91% of ADM-ILD patients had elevated LDH. OP is the most common ILD radiologic pattern, and anti-MDA5 was the most commonly detected autoantibody in ADM-ILD patients, followed by anti-PL-7, anti-Jo-1, anti-PL-12 and anti-EJ. In addition, we divided ADM-ILD into two groups and demonstrated that ADM-ILD with anti-MDA5-positive patients had higher levels of ALT, AST, LDH and CK-MB but had lower levels of WBC, lymphocyte count and ALB.
ADM-ILD patients with MDA5 positivity had higher risk for RP-ILD than those with other myositis-specific antibody positivity,
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.
Clinical effects of direct hemoperfusion using a polymyxin B-immobilized fiber column in clinically amyopathic dermatomyositis-associated rapidly progressive interstitial pneumonias.
analyzed 47 Japanese patients with DM-ILD, including 19 ADM-ILD patients. They found that early CsA treatment was associated with better survival in patients with ADM-ILD, and the 5-year survival rate was as high as 75%. Recent studies have shown that tofacitinib may be beneficial to patients with ADM-ILD who are anti-MDA5 positive,
and the 6-month survival rate is as high as 60–100%. Therefore, early diagnoses and timely treatment are very important to reduce the mortality of ADM-ILD.
ADM with anti-MDA5 antibodies had the characteristic skin rash of the disease, Gottron's sign and heliotrope rash
Recommendations for the treatment of anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated rapidly progressive interstitial lung disease.
; however, Gottron's sign and heliotrope rash did not appear in all ADM patients. Our present study showed that 57.58% and 48.48% of AMD-ILD patients developed Gottron's sign and heliotrope rash, respectively. In addition, most ADM-ILD patients first visit the respiratory department because of shortness of breath, cough, fever and other symptoms, and non-rheumatologists may not notice these characteristic rashes. Consequently, patients may be diagnosed with only IIPs or interstitial pneumonia with autoimmune features (IPAF), resulting in missed opportunities for active treatment and close monitoring and disease progression over time. In our study, we found that ADM-ILD patients had higher LDH levels than other CTD-ILD patients; in 90.91% of ADM-ILD patients, the LDH level exceeded the normal reference value, while this value was exceeded in only 28.42% of other CTD-ILD patients. Furthermore, subgroup analysis showed that ADM-ILD patients with or without anti-MDA5 positivity had higher LDH levels than other CTD-ILD patients. Previous studies have also shown that LDH is elevated in ADM-ILD and is related to a poor prognosis.
Clinical effects of direct hemoperfusion using a polymyxin B-immobilized fiber column in clinically amyopathic dermatomyositis-associated rapidly progressive interstitial pneumonias.
HRCT score and serum ferritin level are factors associated to the 1-year mortality of acute interstitial lung disease in clinically amyopathic dermatomyositis patients.
This suggests that ILD patients with an LDH increase above the normal reference value should be alert to the possibility of ADM-ILD. Therefore, for patients with suspected CTD-ILD and with elevated LDH, MSAs and MAAs need to be tested.
ILD is a common complication of ADM that results in high mortality.
HRCT score and serum ferritin level are factors associated to the 1-year mortality of acute interstitial lung disease in clinically amyopathic dermatomyositis patients.
Clinical features and poor prognostic factors of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with rapid progressive interstitial lung disease.
Incidence and predictive factors for malignancies in 136 Japanese patients with dermatomyositis, polymyositis and clinically amyopathic dermatomyositis.
Our study showed that ADM-ILD patients are more prone than patients with other CTD-ILD to OP radiologic patterns on chest CT scans. Previous studies have shown that ADM-ILD with anti-MDA5 antibodies is characterized by predominant subpleural and lower consolidation, random ground glass opacity (GGO) and the absence of intralobular reticular opacities and honeycomb,
HRCT score and serum ferritin level are factors associated to the 1-year mortality of acute interstitial lung disease in clinically amyopathic dermatomyositis patients.
also found that the OP pattern was more common in patients with anti-MDA5 antibodies than in those without anti-MDA-5 antibodies, which is consistent with our research. Therefore, imaging findings of OP radiologic patterns are highly suggestive of ADM-ILD in CTD-ILD.
Previous studies have reported that ADM patients mostly have anti-MDA5-positive autoantibodies,
HRCT score and serum ferritin level are factors associated to the 1-year mortality of acute interstitial lung disease in clinically amyopathic dermatomyositis patients.
Anti-PL-7 (anti-threonyl-tRNA synthetase) antisynthetase syndrome: clinical manifestations in a series of patients from a European multicenter study (EUMYONET) and review of the literature.
Our study also showed that anti-MDA5 was the most commonly detected autoantibody, but anti-ARS was not rare. In addition, anti-MDA5-positive patients tend to have a younger onset age, and levels of ALT, AST and LDH were higher than those in anti-MDA5-negative patients, while WBC, lymphocyte count and ALB tend to decrease. Besides, the imaging features of anti-MDA5 ADM-ILD were similar to those of viral pneumonia which is sometimes difficult to distinguish from viral pneumonia, especially COVID-19 infection.
Taken together, anti-MDA5 ADM-ILD needs to be considered when an ILD radiologic pattern of OP or NSIP with high levels of LDH, ALT and AST but low levels of WBCs and lymphocytes are observed.
There are several limitations to our study. First, it was a retrospective study, and the number of enrolled patients was small; therefore, it is possible that our findings do not represent the findings in larger patient populations. Second, limited clinical and laboratory data were available for review, and we did not analyze the correlation between the HRCT findings and histopathologic findings. Third, there was no comparison of forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) between ADM-ILD and other CTD-ILD, mainly because data for these key parameters of pulmonary function were missing for many of our patients. Fourth, some negative or positive associations in the statistical analyses may have been due to inadequate power due to the small sample size. Therefore, a prospective study with a substantially larger sample size and a randomized controlled trial are needed to further validate our findings.
Conclusions
In conclusion, our study found that ADM-ILD patients have higher serum LDH, AST and CK-MB levels and are more prone to OP radiologic patterns on chest HRCT scans than other CTD-ILD patients. A high level of serum LDH with ILD may be a useful characteristic index to prompt ADM-ILD. Therefore, ADM-ILD should be considered when patients with ILD have (1) Gottron's sign or heliotrope rash; (2) an ILD radiologic pattern of OP or NSIP or a mixture of the two; and (3) an unexplained increase in serum LDH above the relevant upper limit of normal.
Funding
This research was supported by Zhejiang Provincial Natural Science Foundation of China (No. LBY22H180004) and Natural Science Foundation of Ningbo (No. 2019A610228).
Supplement 1. ADM-ILD patients with or without anti-MDA5 positivity had significantly higher LDH levels than other CTD-ILD patients. *: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001.
CRediT authorship contribution statement
Tingting Wu: Conceptualization, Formal analysis, Data curation, Writing – original draft. Haijun Zhou: Data curation, Conceptualization, Formal analysis. Suling Xu: Data curation, Conceptualization, Formal analysis. Zaichun Deng: Conceptualization, Formal analysis. Yun Zhang: Data curation. Qunli Ding: Conceptualization, Formal analysis.
Declaration of Competing Interest
All authors have no conflicts of interest to disclose.
Acknowledgements
We thank Prof.Chao Chao (Ningbo First Hospital Ningbo, China) for providing 18 cases of ADM-ILD cases. We also thank Dr Shengde Deng (The Affiliated Hospital of Medical School of Ningbo University, China) for providing the review of chest imaging data.
Would a new name hasten the acceptance of amyopathic dermatomyositis (dermatomyositis sine myositis) as a distinctive subset within the idiopathic inflammatory dermatomyopathies spectrum of clinical illness?.
Differential clinical features of patients with clinically amyopathic dermatomyositis who have circulating anti-MDA5 autoantibodies with or without myositis-associated autoantibodies.
Anti-melanoma differentiation-associated gene 5 is associated with rapidly progressive lung disease and poor survival in US Patients with amyopathic and myopathic dermatomyositis.
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.
Clinical effects of direct hemoperfusion using a polymyxin B-immobilized fiber column in clinically amyopathic dermatomyositis-associated rapidly progressive interstitial pneumonias.
Early intervention with corticosteroids and cyclosporin A and 2-hour postdose blood concentration monitoring improves the prognosis of acute/subacute interstitial pneumonia in dermatomyositis.
An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
Recommendations for the treatment of anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated rapidly progressive interstitial lung disease.
HRCT score and serum ferritin level are factors associated to the 1-year mortality of acute interstitial lung disease in clinically amyopathic dermatomyositis patients.
Clinical features and poor prognostic factors of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with rapid progressive interstitial lung disease.
Incidence and predictive factors for malignancies in 136 Japanese patients with dermatomyositis, polymyositis and clinically amyopathic dermatomyositis.
Anti-PL-7 (anti-threonyl-tRNA synthetase) antisynthetase syndrome: clinical manifestations in a series of patients from a European multicenter study (EUMYONET) and review of the literature.