Abstract
Background
Juvenile dermatomyositis (JDM) is an inflammatory vasculopathy characterized by muscle weakness and systemic inflammation. This study aimed to investigate the clinical utility of neutrophil activation markers, specifically calprotectin (S100A8/A9) and myeloperoxidase (MPO)-DNA complexes, as potential biomarkers for muscle inflammation and predictors of muscle outcomes in JDM.
Findings
Plasma levels of calprotectin and MPO-DNA were quantified using ELISA in JDM (n = 36), juvenile idiopathic arthritis (JIA, n = 13), and healthy controls (HCs, n = 21). Disease severity and muscle function were assessed using the Childhood Myositis Assessment Scale (CMAS), Physician Global Assessment (PGA), and Manual Muscle Testing 8 (MMT8). JDM patients exhibited significantly higher plasma calprotectin and MPO-DNA levels as compared to HCs (p = 0.0008 and p = 0.0048, respectively). Calprotectin levels correlated with muscle function scores (CMAS r=-0.682, p = 0.0002; MMT8 r=-0.59, p = 0.005; and PGA muscle scores r = 0.452, p = 0.014). Patients with elevated levels of both calprotectin and MPO-DNA tended to have greater disease activity and muscle involvement. Exploratory ROC analysis suggested that baseline calprotectin and MPO-DNA levels may help distinguish active disease. Notably, higher baseline levels of these markers correlated with improved MMT8 scores over time (r = 0.634, p = 0.027; r = 0.582, p = 0.047), suggesting an association with greater subsequent improvement in muscle strength.
Conclusions
These findings highlight calprotectin and MPO-DNA as potential biomarkers for JDM muscle inflammation and functional outcomes. These results suggest that neutrophil activation plays a key role in JDM pathogenesis and may provide insights into disease monitoring and treatment strategies.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12969-025-01152-w.
Keywords: Juvenile dermatomyositis, Neutrophil, NETs, Biomarkers
Introduction
Juvenile dermatomyositis (JDM) is the most common idiopathic inflammatory myopathy (IIM) in children, characterized by muscle weakness and skin rashes. Beyond musculoskeletal involvement, JDM can affect multiple organ systems, with outcomes ranging from self-limited episodes to chronic progressive disease, leading to disability and calcinosis [1]. Despite immunosuppressive therapy, some patients experience persistent activity and functional impairment, highlighting the need for reliable biomarkers.
JDM pathogenesis involves dysregulated T and B-cell responses and type I interferon signaling [2]. Neutrophils also contribute via formation of neutrophil extracellular traps (NETs)—chromatin structures containing proteins such as myeloperoxidase (MPO) and calprotectin (S100A8/A9)—which promote inflammation and tissue injury [3]. Transcriptomic and proteomic studies show increased NET formation in JDM, possibly driven by immune complexes and sustained by impaired NET clearance [3, 4]. Elevated low-density granulocytes and NETs correlated with disease activity and muscle damage, highlighting neutrophil activation in JDM progression [5].
Calprotectin, a neutrophil-derived alarmin, is elevated in plasma and correlates with disease activity and dyslipidemia [3]. However, the utility of calprotectin and MPO-DNA as markers of muscle involvement and predictors of outcome remains unclear.
We measured plasma calprotectin and MPO-DNA in JDM patients and compared them to juvenile idiopathic arthritis (JIA) and healthy controls (HCs). We assessed their associations with muscle function and disease progression, exploring their potential as biomarkers of muscle inflammation and predictors of muscle function.
Method
Participants and ethics approval
We analyzed banked plasma samples from children with JDM (n = 36) and JIA (n = 13) from Seattle Children’s Hospital, and healthy controls (HCs, n = 21) from the Cure Juvenile Myositis Biorepository. Patient demographics and treatment information are provided in Table 1. Disease activity was assessed using the Childhood Myositis Assessment Scale (CMAS) [6], Physician Global Assessment of Disease Activity (PGA) muscle, skin and overall [7], Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) [8] and Manual Muscle Testing 8 (MMT8) [9]. Following the Pediatric Rheumatology International Trials Organization (PRINTO) criteria for clinically inactive disease in JDM [10], a CMAS score ≥ 48 was considered inactive and ≤ 47 was considered active. For PGA, a score of 0 indicates no disease activity, whereas ≥ 1 indicates active disease [7].
Table 1.
Baseline characteristics of included subjects
| Variables | JDM n = 36 |
JIA n = 13 |
HC n = 21 |
|---|---|---|---|
| Demographics | |||
| Age (years), Median (IQR) | 9.7(6.3, 14.9) | 11.8(8.1, 14.2) | 13.8(9.5, 16.5) |
| Age of onset (years), Median (IQR) | 4.6(3.2, 7.3) | 3.2(2.3, 7.2) | / |
| Female, n (%) | 25(70) | 10(77) | 12(57) |
| Disease duration (months), median (IQR) | 37.6(6.8, 99.5) | 96.7(44.2, 166.8) | / |
| Race, n (%) | |||
| White | 29(81) | / | 17(81) |
| Asian | 1(3) | / | 2(10) |
| Black | 2(6) | / | 2(10) |
| Unknown | 4(11) | 13(100) | / |
| MSA, n (%) | |||
| Anti-NXP2, n (%) | 8(22) | / | / |
| Anti-Mi2, n (%) | 8(22) | / | / |
| Anti-TIF1γ, n (%) | 10(28) | / | / |
| Anti-MDA5, n (%) | 0(0) | / | / |
| MSA(-), n (%) | 11(31) | ||
| Clinical parameters, median (IQR) | |||
| PGA (0–10) | 1(0, 2) | / | / |
| PGA muscle (0–10) | 0(0,1) | / | / |
| PGA skin (0–10) | 0(0,1) | / | / |
| CDASI (0-100) | 1(0, 5) | / | / |
| CMAS (0–52) | 51(48, 52) | / | / |
| MMT8 (0-150) | 144(139, 149) | / | / |
| Patient on treatment currently, n (%) | |||
| Glucocorticoids | 31(89) | / | / |
| Methotrexate | 17(47) | / | / |
| Mycophenolate Mofetil | 11(31) | / | / |
| Hydroxychloroquine | 22(61) | / | / |
| Adalimumab | 3(8) | / | / |
| Abatacept | 8(22) | / | / |
| Rituximab | 2(6) | / | / |
| Biologic Immunoglobulin | 14(39) | / | / |
Follow-up data were available for 17 JDM patients (median duration 1.12 years; IQR 0.51–1.68). Disease progression (%/year) was calculated as [(Parameter follow−up – Parameter baseline)/years of follow-up] × 100.
ELISA-based methods
Calprotectin (S100A8/A9) was analyzed using a commercial ELISA kit according to the manufacturer’s instructions (R&D Systems, Minneapolis MN, USA). Circulating NETs were quantified using an MPO-DNA ELISA, as described previously [11, 12]. Briefly, high-binding 96-well ELISA plates were coated with anti-MPO antibody (4 µg/mL; Mybiosource, San Diego, CA) overnight at 4℃, blocked with 1% BSA in PBS, and incubated with diluted plasma samples (1:10 in 1% BSA-PBS with 2mM EDTA) overnight at 4℃. Anti-DNA-HRP (Roche) was used as a secondary antibody, and detection was performed using TMB substrate (BD Biosciences) with absorbance measured at 450 nm (Synergy 2, BioTek). Known concentrations of MPO-DNA complexes (rhMPO, R&D Systems, Minneapolis, MN, USA; calf-thymus DNA, Trevigen, Gaithersburg, MD, USA) were used to construct a standard curve.
Statistical analyses
Analyses were performed with GraphPad Prism and SPSS. The Kruskal‒Wallis and Mann‒Whitney U tests were used to assess group differences; Spearman’s correlation was used to evaluate associations. ROC curves were used to assess diagnostic performance. The level of significance was set at p < 0.05.
Results
Elevated plasma neutrophil activation markers in JDM are associated with disease activity and muscle function
To assess neutrophil activation in JDM, we quantified plasma calprotectin (S100A8/A9) and MPO-DNA levels and compared them with levels in JIA patients and HCs. Both markers were significantly increased in JDM compared to HCs (calprotectin: p = 0.0008; MPO-DNA: p = 0.0048), whereas MPO-DNA was also elevated in JIA (p = 0.0179) (Figs. 1A-B). A moderate correlation was observed between calprotectin and MPO-DNA in JDM (r = 0.45, p = 0.006), but not in JIA (r = −0.03, p = 0.92) (Figures S1A-B). These results confirm neutrophil activation in JDM, consistent with prior work [3].
Fig. 1.
Neutrophil activation levels in JDM and associations with disease activity markers. A, B Levels of calprotectin (A) and MPO-DNA (B) in plasma among different groups. C Correlation of calprotectin with CMAS, MMT8, and PGA muscle score. D ROC curves comparing the performance of calprotectin, MPO-DNA and CK levels in distinguishing active from remission states in JDM patients based on CMAS. Active disease was defined as a CMAS ≤ 47. (E-F) PGA muscle scores (E) and CMAS (F) in JDM patients stratified into three groups based on neutrophil activation marker levels. Group 0: low level of both calprotectin and MPO-DNA; Group 1: elevated level of either biomarker; Group 2: elevated levels of both biomarkers. Statistical analyses by Kruskal-Wallis test, Spearman correlation and Mann-Whitney U test with * p < 0.05, ** p < 0.01, and *** p < 0.001
Calprotectin correlated negatively with CMAS and MMT8 scores, and positively with PGA-muscle scores, but not with PGA-skin or overall scores (Fig. 1C, Table S1). For detailed correlation analyses involving MPO-DNA, refer to Table S1. Furthermore, JDM patients with active muscle involvement (PGA-muscle ≥ 1) had significantly higher calprotectin than HCs (p = 0.004; Figure S1C). These findings suggest that elevated calprotectin levels are associated with muscle inflammation, rather than skin manifestations, in JDM.
ROC analysis showed calprotectin (AUC = 0.85, p = 0.01) and MPO-DNA (AUC = 0.80, p = 0.03) outperformed creatine kinase (CK) in distinguishing active versus inactive disease (Fig. 1D). Exploratory cutoffs of 373 ng/mL (calprotectin) and 1505 pM (MPO-DNA), sensitivity reached 83% and 100%, respectively, both with 68% specificity. These thresholds require external validation before clinical application.
Based on the 90th percentile of HCs, we stratified patients into three groups: Group 0 (low both markers), Group 1 (elevated either), and Group 2 (elevated both; Table S2). Group 2 had significantly higher PGA-muscle scores than Group 0 (p = 0.0232) and Group 1 (p = 0.0481), and lower CMAS than Group 1 (p = 0.0325) (Figs. 1E-F). These findings suggest that dual elevation of neutrophil activation markers may help identify patients with more active muscle disease. However, given the small sample size (n = 8 in Group 2) and lack of adjustment for potential confounders, this observation should be interpreted with caution.
Baseline neutrophil activation markers are associated with muscle function improvement in JDM
To assess prognostic value, we examined whether baseline neutrophil activation markers were associated with muscle function improvement. Baseline calprotectin and MPO-DNA levels correlated positively with MMT8 improvement in JDM (calprotectin: r = 0.634, p = 0.027; MPO-DNA: r = 0.582, p = 0.047) (Figs. 2A-B), suggesting that higher baseline levels are associated with better muscle outcomes. These associations remained directionally consistent in sensitivity analyses adjusting for age, follow-up duration, and baseline MMT8 (Supplementary Table S3), although effect sizes were attenuated and calprotectin was no longer statistically significant after adjusting for baseline MMT8.
Fig. 2.
Correlations of neutrophil activation markers and disease progression in JDM. A-B Correlation analysis between plasma levels of calprotectin (A) and MPO-DNA (B) and MMT8 progression in JDM. Statistical analyses by Spearman correlation
Discussion
Our findings demonstrate neutrophil activation in JDM, with plasma calprotectin and MPO-DNA correlating with muscle function. These markers may serve as novel biomarkers for muscle activity.
JIA is a common pediatric rheumatic disease primarily affecting joints, with chronic inflammation and sometimes elevated neutrophil activation [13, 14], but distinct from JDM in its clinical presentation. In this study, JIA served as a disease comparator group. Calprotectin was not significantly elevated in JIA, possibly due to limited sample size and subtype heterogeneity.
Serum calprotectin has been proposed as a biomarker in JDM [15]. However, serum measurements may be influenced by platelet activation during coagulation, leading to artificially increased biomarker levels [16, 17]. Our plasma-based approach provides a more accurate assessment. A recent study in JIA directly compared serum and plasma calprotectin, demonstrating that plasma measurements are less affected by in vitro release and better reflect disease activity [18]. All plasma samples were processed under standardized conditions and stored at −80 °C for less than 5 years, a period over which calprotectin and MPO-DNA have been reported to remain stable [19, 20].
ROC curve analysis suggested that neutrophil activation markers may have better diagnostic performance than CK in distinguishing active disease. However, these markers reflect different biological processes from CK and are therefore more likely to serve as complementary tools rather than replacements. Stratification by neutrophil biomarker levels revealed significant differences in baseline muscle involvement, laying the groundwork for improved assessment and individualized treatment. Larger studies are needed to validate these findings and explore their predictive value.
Given the strong association between peripheral neutrophil activation and muscle dysfunction, we hypothesize that neutrophils infiltrate muscle tissue and cause muscle damage directly. Calprotectin, predominantly released by neutrophils and monocytes, has been implicated in muscle pathology. In vitro, it inhibits proliferation and differentiation while inducing apoptosis of C2C12 myoblasts [21]. Immunoreactivity studies in myositis biopsies show calprotectin expression mainly in CD68 + macrophages, while CD15 + neutrophils are rare, likely due to rapid turnover [15, 21]. However, our previous work using electron microscopy confirmed neutrophil infiltration in affected muscle tissue, where they engulf deposited calcium crystals [3]. Moreover, the transcriptomic evidence of an enhanced neutrophil gene signature in muscle biopsies correlating with muscle injury and interferon gene activation [5], further supports the pathogenic role of neutrophils. Additionally, MPO has been detected in DM muscle biopsies as well, primarily localized around endomysial capillaries and perifascicular atrophy. In vitro, MPO could promote inflammation and induce myotube atrophy, further contributing to muscle damage [22]. Collectively, these findings suggest that NETs may form within muscle tissue, exacerbating muscle injury.
Previous studies have shown that circulating NETs correlate with skin disease activity in DM and are associated with myositis-specific autoantibodies (MSAs), particularly anti-MDA5 [5]. These antibodies promote NET formation and are detected in affected tissues, including muscle, lung, and skin [5]. In our cohort, none of the patients tested positive for anti-MDA5, and most had only mild skin involvement, which likely limited our ability to detect associations between neutrophil activation markers and skin disease activity. Additionally, the inherent heterogeneity of JDM and potential differences in immune mechanisms driving skin versus muscle involvement may have further obscured this relationship. Moreover, we did not observe significant differences in calprotectin or MPO-DNA levels among MSA subgroups (Figure S2B), which may also reflect limited sample size. Future research with larger cohorts and detailed MSA subgroup analyses are warranted to clarify the relationship between neutrophil activation and skin involvement in JDM.
Interestingly, we observed baseline NET levels correlated with improved muscle outcomes, suggesting early neutrophil activation may promote repair [23]. Additionally, MPO can reduce neutrophil adhesion and migration, potentially limiting excessive neutrophil accumulation and preventing further muscle injury [24]. These observations underscore the context- and time-dependent dual role of neutrophils in muscle pathology—exacerbating damage during acute inflammation, yet supporting tissue remodeling and functional recovery during later phases. Similar associations have been noted in rheumatoid arthritis (RA), where elevated baseline neutrophil elastase (NE)–DNA and calprotectin predict better treatment responses [25]. However, it is also possible that patients with higher baseline neutrophil activation had more severe disease at presentation and consequently received more intensive immunosuppressive therapy, resulting in greater improvement over time. Thus, the observed association may be at least partially confounded by differences in treatment intensity or approach. Further studies with larger cohorts and detailed treatment data are needed to disentangle the effects of disease severity, treatment, and neutrophil activation on muscle outcomes in JDM.
Our study has limitations. First, most patients in our cohort had only mild disease activity at baseline, which limits the ability to detect robust associations between neutrophil activation markers and disease activity measures, particularly for skin involvement. Second, the low calcinosis prevalence (2/36) in our cohort limits our ability to assess the role of NETs in chronic complications [3, 26]. Third, while the follow-up cohort offers preliminary observations, the small sample size (17 patients, of whom only 12 had MMT8 data) and the minimal decline in MMT8 scores (1/12) reduce the statistical power to detect associations. Larger and longitudinal cohorts are needed to validate these findings.
In summary, our study identifies neutrophil activation markers as potential JDM biomarkers, emphasizing their role in muscle inflammation and disease monitoring. Targeting this pathway may mitigate disability and improve outcomes.
Supplementary Information
Acknowledgements
We are grateful to all patients for consenting to biospecimen and data collection. JS and YW acknowledge support from the China Scholarship Council Program (Project ID: 202306210294, 202306210397).
Abbreviations
- JDM
Juvenile Dermatomyositis
- NETs
Neutrophil Extracellular Traps
- MSAs
Myositis-Specific Autoantibodies
- MPO
Myeloperoxidase
- S100A8/A9
Calprotectin
- ELISA
Enzyme-Linked Immunosorbent Assay
- JIA
Juvenile Idiopathic Arthritis
- HCs
Healthy Controls
- IRB
Institutional Review Board
- PGA
Physician Global Assessment
- CMAS
Childhood Myositis Assessment Scale
- MMT8
Manual Muscle Testing 8
- CDASI
Cutaneous Dermatomyositis Disease Area and Severity Index
- CK
Creatine Kinase
- ROC
Receiver Operating Characteristic
- AUC
Area Under the Curve
Authors’ contributions
J.S. and C.L. conceived and designed the study.Y.W., T.W., S.S., A.L., P.H., and J.C. collected patient information.Y.W., A.J., P.H., and J.C. performed the experiments.J.S. and C.L. analyzed and interpreted the data.J.S. and Y.W. wrote the initial manuscript draft.Q.W. and C.L. supervised the project and acquired funding.All authors reviewed and edited the manuscript.
Funding
This study was supported by CAMS Innovation Fund for Medical Sciences (CIFMS) (2023-I2M-C&T-B-035, 2023-I2M-2-005) to QW, and CureJM Foundation and the Myositis Association to CL. Cure JM Foundation also supports the Myositis Center of Excellence at Seattle Children’s Hospital. Samples from healthy individuals were generously supplied by the Stanley Manne Children’s Research Institute/Ann & Robert H. Lurie Children’s Hospital of Chicago Cure Juvenile Myositis Biorepository/Registry. CL is a Herndon and Esther Maury Endowed Professor of Rheumatoid Arthritis, with the endowment supporting some of his salary for this study.
Data availability
The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
All samples were obtained with informed consent under University of Washington IRB approval (#3100).
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jia Shi and Yang Wu these authors contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data supporting the findings of this study are available from the corresponding author upon reasonable request.