Introduction
Juvenile dermatomyositis (JDM) is an uncommon immune-mediated systemic autoimmune vascular disorder characterized by symmetrical proximal muscle weakness, elevated serum muscle enzymes, and distinctive cutaneous manifestations such as Gottron papules and heliotrope rash [
1]. This disease can also involve multiple internal organs, including the lungs, joints, heart, and gastrointestinal tract [
2,
3]. In adults, interstitial lung disease (ILD) is a frequent complication of myositis, with a prevalence ranging from 30 to 50%, particularly prominent in Asian populations [
4]. ILD in this context carries a substantial burden of morbidity and mortality, with rapidly progressive ILD being the leading cause of death [
5,
6]. However, the prevalence of ILD in children with JDM is comparatively lower. The diagnostic evaluation primarily relies on imaging modalities such as chest computed tomography (CT), along with bronchoscopy and lung biopsy if necessary. And most children with JDM-ILD experience a chronic progressive course ILD [
7,
8].
In children with JDM-ILD, initial lung involvement often presents as either asymptomatic or with mild symptoms. However, as the disease advances, clinical manifestations associated with ILD gradually emerge. Ultimately, there is a progressive decline in the functional units of the alveolar capillary system, which becomes challenging to reverse [
8]. Therefore, early detection and timely intervention of JDM-ILD can significantly improve the long-term prognosis in children. Given the limited use of bronchoscopy and lung biopsy as invasive examinations in children, early diagnosis of JDM-ILD currently depends on chest high-resolution CT (HRCT) scans for assessing disease extent and monitoring progression [
9‐
12]. However, the insidious nature of the onset of JDM-ILD makes early recognition difficult, and the radiation effects on children caused by multiple HRCTs over a certain period of time cannot be ignored. The pathogenesis of JDM-ILD is not clear, but numerous studies have suggested that its development involves multiple immune cells, cytokines and autoantibodies, and is highly associated with its own inflammatory activity [
13,
14].
The primary goal of this study is to establish a clinical prediction model for JDM-ILD by analyzing relevant non-invasive clinical characteristics. The proposed model endeavors to assess the risk of JDM-ILD in affected patients, facilitate early detection of JDM-ILD, and predict the long-term prognosis by utilizing risk modeling. This approach enables personalized care for children with JDM-ILD, including tailored treatment plans and individualized follow-up strategies based on comprehensive risk model and prognostic assessment.
Discussion
ILD is a prevalent and severe complication in children with JDM, significantly impacting their quality of life and prognosis, particularly in anti-MDA5 positive JDM patients [
19‐
21]. While the incidence of ILD in JDM is relatively lower compared to adult DM, [
22] the development of ILD in children can result in profound and irreversible pulmonary impairments [
20]. In this retrospective study, three clinical features, including ESR, IL-10, and MDA-5 antibody, were extracted to construct a discriminative nomogram. The model exhibited strong predictive performance in assessing the risk of JDM-ILD. Additionally, the model demonstrated notable clinical utility and provided prognostic information for JDM in clinical practice. We propose ESIM, a predictive model utilizing the fitted discriminative nomogram of ESR, IL-10, and MDA-5 antibody, for assessing the risk of developing JDM-ILD. The implementation of the ESIM model has the potential to facilitate early detection and individualized treatment approaches for children with JDM-ILD.
Myositis-specific antibodies, including NXP2, MDA5, Jo1, etc., have gained prominence in the clinical distinction of dermatomyositis. MDA5, encoded by the IFIH1 gene, [
23] is reported to be positive in approximately 11–60% of dermatomyositis cases, with a positivity rate of 6-12% in children. Notably, MDA5 antibody positivity is more prevalent in Asian populations compared to white populations [
24]. The anti-MDA5 antibody serves as a valuable biomarker for ILD in JDM and can also predict ILD complications [
25]. Consistent with previous studies, the study also revealed a significant association between MDA5 positivity and the presence of JDM-ILD in children. Patients with MDA5-positive DM are at a high risk of developing rapidly progressive interstitial lung disease (RP-ILD) and have a poor prognosis, with an early-stage mortality rate of approximately 50% [
23,
26,
27]. In our study, the occurrence of RP-ILD leading to mortality was rare. These findings also suggest that children with MDA5-positive JDM-ILD may have a more favorable prognosis compared to adults with DM.
JDM is a chronic systemic autoimmune disease associated with the involvement of various inflammatory factors. In DM-ILD patients, particularly those positive for MDA-5 antibodies, researchers have observed elevated levels of interleukin, specifically IL-6 and IL-10, which are pro-inflammatory cytokines [
28,
29]. These cytokines are closely linked to disease activity and have the potential to induce alveolar epithelial cell injury through macrophage activation or other pathways, leading to the development of pulmonary fibrosis and subsequent ILD [
30]. ESR serves as an unspecific biomarker of the acute phase response, offering valuable information during the active phase of JDM [
31,
32]. ESR has been proposed as a serum indicator for assessing disease activity and facilitating early discrimination in JDM [
33,
34]. However, some researchers have been suggested that the elevated ESR in DM patients is not directly correlated with the degree of inflammatory muscle damage but may instead indicate the severity of pulmonary involvement [
35]. The secretion of cytokines by inflammatory cells in the muscle tissue of children with JDM is minimal, and detectable levels of cytokines and ESR are observed only when ILD is present [
36]. The study demonstrated a significant elevation of IL-10 and ESR in JDM-ILD patients. The early discriminant model incorporated IL-10 and ESR as important factors, particularly in children with positive MDA-5 antibodies. We have incorporated three independent risk factors into a novel discriminative model, the ESIM model, for the purpose of risk assessment in JDM-ILD. Based on the assessment of the ESIM model, we evaluated a cut-off value of 88 points for clinical application in diagnosing JDM-ILD. For instance, if a JDM patient has a positive anti-MDA5 antibody (34 points), an ESR ≥ 20 mm/h (29 points), and an IL-10 ≥ 6.9 pg/ml (25 points), their total score would reach 88 points, indicating the requirement for meticulous clinical surveillance of concurrent ILD. Currently, there is no consensus on the standardized screening of ILD in children with JDM. Pulmonary function tests and chest HRCT are useful tools, but their interpretation and timing of review are still controversial [
37]. Thus, identifying high-risk groups based on the ESIM model at the time of diagnosis is essential.
Despite the low mortality rate in children with JDM-ILD, it is essential to prioritize the long-term lung effects and quality of life of these patients. Currently, there is a lack of well-defined and individualized treatment strategies for children with JDM-ILD. Our discriminant model offers valuable insights into disease severity, aiding clinical decision-making and personalized treatment strategies. The nomogram score derived from the model serves as a prognostic indicator, enabling the development of individualized follow-up plans. Higher scores indicate the need for more frequent monitoring to promptly identify and address potential complications.
This study has several limitations. Firstly, although previous studies have identified additional risk factors such as positive anti-Jo-1 antibody and elevated CRP for the development of complicated ILD, [
38] our study did not find significant differences in these indicators. Given the limited number of studies focused on children compared to adults, it is essential to expand the sample size in future investigations. Secondly, assessing the prognosis of children with JDM-ILD only based on mortality is challenging, as the incidence of JDM-ILD progressing to rapidly progressive ILD leading to death is much lower in children. Furthermore, the subjective nature of assessing deterioration in children used in our study may introduce bias into the results. Thirdly, our sample was drawn from a single treatment center, which may limit the generalizability of the findings to the broader population. Lastly, the relatively rare onset of JDM-ILD resulted in some children not being screened for MSA, and their data were considered negative by default, potentially introducing bias into the analysis. Future research should address these limitations to enhance the robustness and generalizability of the findings.
In conclusion
This study established a discriminative nomogram for JDM-ILD based on the ESIM model including ESR, MDA-5, and IL-10 in enrolled children, providing clinical guidance for evaluating JDM-ILD and predicting long-term prognosis.
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