Background
Dermatomyositis (DM) is a systemic, heterogeneous disease that presents with skeletal muscle weakness, typical skin lesions, and other internal organ damage, usually with specific autoantibodies. The autoantibody against melanoma differentiation-associated gene 5 (anti-MDA5ab), first discovered by Sato et al. in 2005, has attracted extensive attention due to its association with the specific form of DM known as amyopathy or hypomyopathy [
1].
Interstitial lung disease (ILD) is one of the most frequent and serious manifestations of MDA5+DM, with a much higher prevalence of 50–100% compared with other types of DM [
2,
3]. The precise pathogenesis of ILD in patients with MDA5+DM remains unclear, although some evidence suggests that pulmonary vasculopathy, anti-MDA5ab-mediated endothelial cell injury, and increased expression of pro-fibrogenic cytokines may be involved [
4‐
6]. Rapidly progressive ILD (RP-ILD) is a refractory and devastating complication and arguably a major cause of death in patients with this disease. In addition, several studies showed that serum ferritin and other cytokine profiles were correlated with the clinical course and complications of MDA5+DM. However, the differing clinical features of MDA5+DM among patients mean that it is hard to clarify disease severity based on a single factor. Some studies have identified phenotypic variations of MDA5+DM by cluster analysis, with patients in different clusters having highly heterogenic manifestations and outcomes. Phenotypes characterized by rashes, arthritis, skin vasculopathy, and serum hypoinflammatory status had a lower risk of death, while phenotypes involving severe pulmonary manifestations were always linked to poor outcomes [
7‐
9].
Patients with autoimmune diseases are particularly vulnerable to infection, possibly because of disorders in the intrinsic immune environment, secondary immunodeficiency due to the use of immunosuppressants, and underlying complications. The timely diagnosis and treatment of infections is critical for the clinical prognosis of these patients.
The current study aimed to investigate and compare the clinical characteristics of patients with MDA5+DM who survived and those who died, to identify potential prognostic predictors in a Chinese cohort of patients with MDA5+DM.
Discussion
Recent research on autoantibodies and clinical practice have produced new insights into the various subtypes of DM associated with different MSAs, which have in turn played important roles in determining the clinical features and assessing the prognosis of DM. MDA5+DM has been widely considered as a more severe subtype compared with other types of DM. In the current study, we sought to determine the risk factors influencing survival in patients with MDA5+DM.
Previous studies have highlighted the clinical features of the acute form of MDA5+DM; data available on the long-term clinical course and hazard factors is minimal. In China, many cohorts used the occurrence of RP-ILD as an endpoint in the studies of MDA5+DM prognosis [
12‐
15]. However, we focus on comparing the data of the patients who deceased and the others who still survived. Mortality is an unequivocal end point which can directly measure deterioration. Long-term follow-up outcome makes it establish more clinically meaningful and reliable proxies for prognosis. For those studies in which death was the primary outcome, the sample size was also significantly smaller in other centers than in this report [
16], except for retrospective multicenter cohorts [
17,
18], and the follow-up time of some studies is shorter [
19,
20].
The overall mortality in the current study was 25.4%, which was similar to several other studies (23.4–37.9%) [
7,
9,
18]. Our data also supported previous studies showing that death was a time-dependent change and often occurred in the early stage of disease [
21]. The high risk of death at this stage highlights the need to strengthen disease-progression monitoring.
The relationship between specific autoantibodies and disease activity or prognosis in idiopathic inflammatory myositis is currently unclear. Gono et al. [
22] found that anti-MDA5ab titers were higher at admission and decreased less after treatment in non-survivors. In contrast, the current study found no significant difference in survival rates in relation to anti-MDA5ab levels at baseline, probably because subjects who received a diagnosis of MDA5+DM usually had high levels determined by semi-quantitative measurements, and differences may become evident if quantitative assays are used. Other studies showed that anti-MDA5ab levels tended to decline significantly at remission but increase again during relapse, suggesting that anti-MDA5ab could be used to evaluate disease activity and response to treatment [
23,
24]. Unfortunately, the current study only evaluated anti-MDA5ab at a single time point and did not track the longitudinal serological changes.
Patients with MDA5+DM also exhibit a high prevalence of anti-Ro52ab. A previous study in a cohort of 267 patients with idiopathic inflammatory myositis-associated ILD found that anti-Ro52ab was more frequent in patients with anti-MDA5 and anti-Jo-1 antibodies than in those with other MSAs [
25]. Xu et al. [
16] showed that anti-Ro52ab was associated with a higher prevalence of RP-ILD in patients with anti-MDA5ab-positive clinically amyopathic dermatomyositis-ILD, while the cumulative 24-month survival rate was lower in patients with anti-Ro52ab than in those without. The current study further demonstrated that patients with MDA5+DM who were strongly positive for anti-Ro52ab tended to have a poorer prognosis. These results suggest that patients with MDA5+DM and anti-Ro52ab are more likely to have a high-risk clinical phenotype, although the cause remains unclear. The presence of anti-Ro52ab may reflect specific subtypes of this disease, and further stratification of patients with MDA5+DM based on the combination of anti-MDA5ab and anti-Ro52ab levels may help to provide more precise treatments and improve the long-term survival of patients.
Lymphocyte subsets play divergent roles in the cell microenvironment to maintain immune homeostasis. Blood lymphocyte counts, both CD4+ and CD8+ T lymphocytes, were significantly lower in patients with MDA5+DM compared with controls, especially in cases with aggravation of interstitial lung lesions [
12,
26]. The current study enrolled patients who were diagnosed and treated for the first time and the use of immunosuppressants was therefore not considered to be responsible for the elimination of immunocytes. Mueller et al. [
27] previously reported that effector memory T cells broadly migrated between peripheral nonlymphoid tissues (e.g., skin and lung), the circulation, and the spleen and emphasized potential differences in the migratory patterns between CD4+ and CD8+ T lymphocytes. In addition, non-recirculating tissue-resident memory T cells could localize within epithelial layers in previously challenged skin and lung airways. Further experiments are needed to determine the detailed mechanism.
The aggravation of primary lung lesions, deterioration caused by excessive immunosuppression, and secondary infection are currently recognized as the main causes of death in patients with MDA5+DM. The current study showed that patients who died of respiratory failure all had a complication of ILD and half also had lung infections. Our study confirmed that RP-ILD was significantly associated with poor survival rates and was the most critical predictor of mortality, with an almost 25-fold increased risk of death. Regarding lung function, all parameters were worse in the non-survival compared with the survival group, but the differences were not significant. This lack of significance may have been attributable to incomplete data.
The clinical management of MDA5+DM is challenging; no standard treatment has yet been established and current treatments are primarily empirical. Until Tsuji et al. [
28] proposed an intensive regimen of “triple therapy,” the 6-month survival rate of patients with MDA5+DM undergoing conventional therapy remained poor. In addition, Janus kinase inhibitors have demonstrated favorable efficacy and safety [
29]. However, the current study did not include a large proportion of patients treated with triple therapy, which may result from the short survival time. The condition of critical patients is prone to progress rapidly in the early stage, and high-dose GCs alone are therefore the primary choice to induce remission; however, their effect is likely to be unsatisfactory, even during active treatment, and the short course of the disease may provide no opportunity to initiate subsequent therapy.
Patients with autoimmune diseases are often susceptible to various infections, possibly due to immune deficiencies. In the current study, infection events occurred more frequently in the non-survival group, and it could be that the dosages of GCs were excessively high since the disease was most active in the early stage. Previous studies showed that underlying lung disease such as ILD might provide an accessible environment for infection [
30]. Lung infection was indeed the most among all types of infection in the non-survivors, all of whom stricken with a lung infection were complicated with RP-ILD, so that dual setbacks led to a great increase in mortality. Moreover, our study found that EBV was common, but many patients lacked symptoms of current acute infection. EBV is usually acquired silently in life span and carried thereafter as an asymptomatic infection; thus, it was uncertain if the infection happened before or after the start of DM. Decreased immune control and increased reactivation of EBV has been found to be a contributing factor in the development of autoimmune diseases [
31,
32]. Advances regarding how EBV infection may interrelate with MDA5+DM deserve attention.
This study had several limitations. It was a retrospective study from a single institution and may thus have included potential bias. In addition, missing data for some items, such as pulmonary function, was unavoidable. However, the study had the advantage of including a relatively large cohort of subjects diagnosed with MDA5+DM, recruited from a tertiary medical center in China, all of whom underwent HRCT, and the outcome for each subject was determined over a sufficiently long follow-up period.
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