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Increased serum level of IL-6 predicts poor prognosis in anti-MDA5-positive dermatomyositis with rapidly progressive interstitial lung disease

Arthritis Research & Therapy volume 26, Article number: 184 (2024) Cite this article

Abstract

Backgroud

Anti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis (anti-MDA5-positvie DM) is a subtype of dermatomyositis with a poor prognosis, characterized by rapidly progressive interstitial lung disease (RP-ILD). The study aims to investigate the significance of serum cytokines profiles and peripheral lymphocytes in predicting prognoses of anti-MDA5-positvie DM with RP-ILD. Furthermore, it seeks to analyze longitudinal data of lymphocytes during hospitalization to identify distinct trajectories and cluster patients accordingly.

Methods

A total of 168 patients with anti-MDA5-positive DM were enrolled in this retrospective study from two cohorts. Univariate and multivariate Cox regression analyses were conducted to determine the predictors of 6-month all-cause mortality and RP-ILD. Group-based trajectory modeling (GBTM) was employed to model the trajectories of longitudinal peripheral lymphocytes.

Results

In the multivariate Cox regression analysis, IL-6 ≥ 13.41pg/mL, lymphocytes < 0.5 × 109 /L, lymphocytes from 0.5 to 1.0 × 109 /L, older age, and elevated LDH were identified as independent predictors of 6-month all-cause mortality. Furthermore, IL-6 ≥ 13.41pg/mL, lymphocytes < 0.5 × 109 /L, and lymphocytes from 0.5 to 1.0 × 109 /L were found to be independent predictors of RP-ILD. Additionally, three trajectory groups of lymphocytes within the first week after admission were established based on GBTM. These groups included: Group 1, with low-level of lymphocytes that declined; Group 2, with medium-level of lymphocytes that slightly rose; and Group 3, with high-level of lymphocytes that rose. Notably, group 1 showed the highest mortality (90.7%) and all experiencing RP-ILD. Increased expression of IL-6 in lung tissues was observed in two cases with RP-ILD compared to two cases without RP-ILD. We also found the increased infiltration of CD4 + and CD8 + T cells, particularly CD8 + T cells, in lung tissues from patients with RP-ILD.

Conclusions

Our study demonstrated that increased level of serum IL-6 (≥ 13.41pg/mL) and severe lymphopenia were promising predictors of 6-month all-cause mortality and the occurrence of RP-ILD in anti-MDA5-positive DM patients. Furthermore, tracking distinct trajectories of lymphocytes during hospitalization can be utilized to cluster patients.

Introduction

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (anti-MDA5-positive DM) is a subtype of dermatomyositis, characterized by specific mucocutaneous manifestations, minimal or absent muscular weakness, and interstitial lung disease (ILD). In Japanese and Chinese cohorts, the prevalence of ILD ranges from 40 to 100% [1, 2]. Rapidly progressive ILD (RP-ILD) occurs in 40–79% of patients with anti-MDA5-positive DM and is the main cause of death [3,4,5,6]. Despite treatment strategies involving glucocorticoids, immunosuppressants and biological and targeted agents, the mortality of patients with RP-ILD is reported to be as high as 50% during the early stage of illness [7, 8]. Interestingly, disease progression tends to improve and recurrence appears to be rare after 6 months from disease onset [8]. However, there is currently no generally recognized clinical classification or predictive biomarkers for anti-MDA5-positive DM. In order to further optimize clinical phenotypes and predict prognosis, it would be valuable to develop the risk stratification to predict the prognosis of RP-ILD in anti-MDA5-positive DM.

Patients with anti-MDA5-positive DM manifest dysregulated autoimmunity, including exacerbated inflammatory response, cytokine release, lymphopenia, monocyte/macrophage activation [9,10,11]. Several studies have uncovered different biomarkers associated with increased disease severity and unfavorable prognosis, such as anti-MDA5 antibody titers [12], ferritin [13], krebs von den Lungen-6 (KL‐6) [14], lactate dehydrogenase (LDH) [3], C-reactive protein [15], YKL-40 [16], soluble CD206 [17], and galectin-9 [18]. However, due to the heterogeneity and complexity of anti-MDA5-positive DM, it remains challenging to rely on a single biomarker for assessing the disease status and prognosis.

Multiple studies have suggested elevated levels of pro-inflammatory cytokines in individuals with anti-MDA5-positive DM when compared to those with other myositis specific autoantibody (MSA)-positive DM. These cytokines include IL-6, IL-8, IL-10, TNF-α, IFN-γ [19, 20]. The increased cytokines are closely linked to disease severity and treatment response [11], and may cause excessive monocyte/macrophage activation, potentially contributing to the underlying mechanisms of anti-MDA5-positive DM [21, 22]. Lymphopenia is a unique feature of anti-MDA-positive DM, which is related to the development of RP-ILD and mortality, indicating potential immune deficiency [4, 23]. A large-scale Chinese cohort study on patients with anti-MDA5-positive DM found that the peripheral lymphocyte count could serve as a simple and promising biomarker for defining distinct subtypes and predicting various outcomes [9]. Nevertheless, the significance of pro-inflammatory cytokines combined with lymphopenia for predicting the prognosis of anti-MDA5-positive DM with RP-ILD remains inadequately understood. This study aims to address the knowledge gap.

In this study, we initially investigated the significance of serum cytokines profiles and peripheral lymphocytes in predicting prognosis. Subsequently, we analyzed longitudinal data of lymphocytes during hospitalization to identify distinct trajectories and cluster patients accordingly. Finally, we examined the histopathological features of lung tissues.

Methods

Study design and population

The retrospective cohort study was conducted at two tertiary centers in southern China. We screened all eligible patients between January 1, 2017 and June 30, 2022, who fulfilled the following criteria: initially met the 1975 Bohan and Peter criteria and the 2017 European League Against Rheumatism/American College classification criteria; with anti-MDA5 bodies positive measured by immunoblotting assay. The exclusion criteria included: (i) lack of a diagnosis of ILD; (ii) presence of other rheumatic connective tissue diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, systemic sclerosis; (iii) absence of serum cytokines profiles data.

The diagnosis of ILD was confirmed based on notable chest high-resolution computed tomography (HRCT) findings, such as ground-glass attenuation, consolidation, traction bronchiectasis, reticulation, and honeycombing. This diagnosis was supported by respiratory symptoms and pulmonary function tests. RP-ILD was defined as acute exacerbation of dyspnea, markedly decreased pulmonary ventilation or diffusion capacity, progressive manifestations on HRCT, and acute respiratory failure within 1 month. Lymphopenia was defined as a peripheral absolute lymphocyte count of less than 1.0 × 109/L based on the laboratory reference of the both hospitals.

Baseline records, including demographic data, laboratory indicators, and radiological features, were collected during the first week of hospitalization through a standardized retrospective review for each patient. Peripheral lymphocytes were recorded at four specific times: 1, 3, 5, 7 days after admission. Outcome data were gathered from medical records and follow-up through outpatient visits or telephone communication.

All patients were followed up for a minimum of 6 months after diagnosis or until death. Previous studies have shown that the 6-month all-cause mortality was considered the endpoint due to the majority of deaths and occurrences of RP-ILD within this time frame [8, 9]. Follow-ups were completed by December 31, 2022, with each patient contacted via telephone to obtain oral consent. This study was approved by the Ethical Committee of the First Affiliated Hospital of Sun Yat-sen University (ID: [2024]396).

Measurement of anti-MDA5 antibody and serum cytokines

Anti-MDA5 antibody was detected with EUROLINE autoimmune inflammatory myopathies Ag (IgG) test kit (EUROIMMUN, Luebeck, Germany) according to the manufacturer’s instructions. Serum cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were measured by the cytometric bead array (CBA) assay. The Human Th1/Th2/Th17 Cytokine Kits were procured from Jiangsu Saiqi Biotechnology Co. Data analysis was performed using FCAP Array software from BD Biosciences in San Jose, CA, USA. The limitations of cytokines detection ranged from 2.5pg/mL to 2500pg/mL.

Pathological analysis

The lung specimens of anti-MDA5-positive DM were collected from three patients through transbronchial lung biopsy and one patient through pneumonectomy. The normal lung specimens were collected from two patients with spontaneous pneumothorax. All lung specimens underwent staining with H&E and Elastica van Gieson stains. Immunohistochemistry was carried out using a 1:200 dilution of rabbit anti-IL-6 polyclonal antibody. The process included deparaffinization, hydration, and antigen retrieval in a pH 6.0 citrate buffer using a microwave oven. Endogenous peroxidase activity was blocked with 3% H2O2 for 25 min at room temperature, followed by incubation in a 3% Bovine Serum Albumin (BSA) solution and overnight staining with rabbit anti-IL-6 polyclonal primary antibodies (Affinity, DF6087) at 4℃. Subsequently, the samples were incubated with a secondary antibody for 50 min. Chromogenic analysis was performed using DAB, and the nuclei were stained with hematoxylin.

Immunofluorescence staining

The formalin-fixed and paraffin-embedded lung tissue sections were deparaffinized and rehydrated through a gradient of ethanol, followed by antigen retrieval (EDTA, pH 9.0) under high temperature and pressure conditions. The sections were immersed in 3% H2O2 solution to block endogenous peroxidase activity. Subsequently, the sections were incubated with the primary CD4 antibodies (Maixin, RMA-0620) at 4°C overnight. After several washes with TBST, the sections were incubated with the secondary goat anti-rabbit IgG antibodies (Abcam, ab205718) at 37°C for 45 min. Following several washes with TBST, the sections were incubated with an appropriate iFluor® 488 tyramide solution for tyramide signal amplification (TSA). The sessions were placed into a preheated box to strip away the tissue-bound primary/secondary antibody complexes, thereby preparing for labeling of the next marker. The above process was repeated for incubation the primary CD8 antibodies (Zhongshanjinqiao, ZA-0508) and the secondary donkey anti-rabbit IgG antibodies. Finally, the sessions were nucleated with 4’, 6-diamidino-2-phenylindole (DAPI) and imaged using a confocal microscope (Olympus, BX53).

Statistical analysis

Statistical analysis was performed using SAS software version 9.4 (SAS Institute, Inc.) and R (version 4.2.2). A two-sided P < 0.05 was regarded as statistically significant. Continuous variables were described as mean (standard deviation) or median (interquartile range), while qualitative variables were presented as frequency (percentage). Parameters between the two groups were compared using independent samples t-test, Mann-Whitney U test, and Chi-square test where appropriate. Multiple comparisons were conducted using one-way ANOVA test, Kruskal-Wallis test, and Chi-square test as appropriate. Univariate and multivariate Cox regression analyses were conducted to identify predictors of death and RP-ILD. Candidate variables for multivariate Cox regression were selected using forward stepwise regression based on maximum likelihood estimation. Restricted cubic splines (RCS) were utilized with four knots (P5, P35, P65 and P95, with P5 as the reference) to examine the dose-response relationship between continuous variables and outcomes, as well as locate crucial key points. The horizontal axis represented change in continuous variables, while the vertical axis depicted the logarithm of the corresponding predictive risk value (lnHR). Kaplan-Meier (KM) curves and the Log Rank-test were employed to compare the cumulative proportion of death and RP-ILD cross various subgroups.

Group-based trajectory modeling (GBTM) was utilized to analyze the trajectories of longitudinally measured peripheral lymphocytes in order to capture their early-stage dynamics and potentially identify distinct subgroups based on these trajectories. Various permutations of polynomials were fitted, ranging from linear to cubic, and from 1 to 5 groups. The optimal model for distinct peripheral lymphocytes trajectories was selected based on several criteria: (i) a Bayesian information criterion (BIC) value closer to 0 indicating better fit, (ii) a Bayesian factor logarithmic value > 6 suggesting differences in fitting results between comparison models, allowing for acceptance of more complex models; a value < 2 indicating acceptance of a simpler model, (iii) an average posterior probability (AvePP) > 0.7, and (iv) consideration of clinical relevance and simplicity.

Results

Characteristics of anti-MDA5-positive patients with ILD

A total of 168 patients with anti-MDA5-positive DM were enrolled in the current cohort, as illustrated in Supplementary Fig. 1. Among them, 72 patients were male, and with an average age of 53.6 (10.4) years old. During the follow-up, 85 (50.6%) patients died cumulatively, while 121 (72.0%) patients developed RP-ILD. Among the deceased patients, 56.5% (48/85) died within the first month after diagnosis, and 34.1% (29/85) passed away in the subsequent 1 to 3 months. Furthermore, 84.3% (102/121) of RP-ILD cases occurred within the first month, while 12.4% (15/121) emerged in the following 1 to 3 months (Supplementary Fig. 2). Among those who experienced RP-ILD, 65.8% (77/117) died within the initial 3 months. The median follow-up duration for survivors was 14.6 months. The primary causes of death in 85 patients were RP-ILD (100%), followed by multiple organ failure syndrome (30.6%), acute heart failure (21.2%), sepsis (12.9%), acute kidney injury (12.9%), and spontaneous bleeding (11.8%).

Upon analysis of the serum cytokine profiles, we observed higher levels of serum IL-6 and IL-10 in the non-survival or RP-ILD group compared to those in the survival or non-RP-ILD group. Additionally, the peripheral lymphocyte count tended to be lower in non-survivors than survivors. There was a significant decrease in lymphocyte count in the RP-ILD group compared to that in the non-RP-ILD group. Both of the peripheral CD4 + and CD8 + T cells were statistically lower in non-survivors or patients with RP-ILD compared to those in survivors or patients with non-RP-ILD, with a notable decrease in CD8 + T cells. Furthermore, patients in the non-survival and RP-ILD group exhibited higher levels of LDH. It is evident that non-survivors and patients with RP-ILD received more glucocorticoid pulse therapy, biological agents and immunoglobulin. The detailed information is demonstrated in Table 1.

Table 1 Clinical characteristics of patients with anti-MDA5-positive DM
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Increased serum level of IL-6 and lymphopenia predicted the 6-month all-cause mortality and occurrence of RP-ILD in patients with anti-MDA5-positive DM

Univariate and multivariate Cox regression analyses were conducted to explore potential risk factors associated with 6-month mortality and RP-ILD in individuals with anti-MDA5-positive DM (Table 2). In the multivariate Cox regression analysis involving continuous variables, serum level of IL-6 (HR 1.004, 95% CI: 1.002–1.006, P < 0.001), lymphocyte count (HR 0.107, 95% CI: 0.045–0.254, P < 0.001), age on onset (HR 1.044, 95% CI: 1.018–1.070, P < 0.001), and LDH (HR 1.001, 95% CI: 1.000–1.002, P = 0.013) were identified as independent predictors of 6-month all-cause mortality. Additionally, serum level of IL-6 (HR 1.002, 95% CI: 1.000–1.004, P = 0.027) and lymphocyte count (HR 0.175, 95% CI: 0.095–0.325, P < 0.001) were found to be independent predictors of RP-ILD.

Table 2 Risk factors of 6-month death and RP-ILD in patients with anti-MDA5-positive DM based on univariate and multivariate Cox regression analyses
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RCS analysis was utilized to model and visualize the relationship between serum IL-6 or peripheral lymphocytes and the outcomes. As shown in Fig. 1, the dose-response curves for serum IL-6 and all-cause mortality exhibited a conspicuous L-shaped correlation and a non-linear trend similar to that for serum IL-6 and RP-ILD (P for non-linearity < 0.001). The risk of mortality and RP-ILD increased rapidly until around 13.41pg/mL of serum IL-6 and then plateaued thereafter (Fig. 1A and B). Conversely, with increased lymphocytes, the mortality appeared linear decreased trend (P for non-linearity = 0.381; Fig. 1C). Additionally, we illustrated a Z-shaped association between lymphocytes and RP-ILD (Fig. 1D). The plot showed a substantial increase in risk associated with lower level of lymphocytes. Specifically, when lymphocyte count exceeded 0.5 × 109/L, the risk of RP-ILD decreased (P for non-linearity < 0.001).

Fig. 1
figure 1

Restricted cubic spline regression on peripheral lymphocytes and the risk of 6-month all-cause mortality (A) and RP-ILD (B) in patients with anti-MDA5-positive DM; Restricted cubic spline regression on serum IL-6 and the risk of 6-month all-cause mortality (C) and RP-ILD (D) in patients with anti-MDA5-positive DM

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In the RCS analysis, both serum level of IL-6 and lymphocyte count were discretized. The cut-point for serum IL-6 was determined to be 13.41pg/mL, while the critical values for lymphocyte count were defined as 0.5 × 109/L and 1.0 × 109/L. Consistent with previous findings, IL-6 ≥ 13.41pg/mL (HR 3.615, 95% CI: 2.059–6.350, P < 0.001), lymphocyte count < 0.5 × 109/L (HR 8.717, 95% CI: 2.040–37.254, P = 0.004), lymphocyte count from 0.5 to 1.0 × 109/L (HR 6.307, 95% CI: 1.494–26.620, P = 0.012), older age (HR 1.555, 95% CI: 1.201–2.015, P < 0.001), and elevated LDH (HR 1.317, 95% CI: 1.085–1.598, P = 0.005) were identified as the risk factors of 6-month all-cause mortality. Furthermore, IL-6 ≥ 13.41pg/mL (HR 2.882, 95% CI: 1.836–4.525, P < 0.001), lymphocyte count < 0.5 × 109/L (HR 6.565, 95% CI: 2.499–17.248, P < 0.001), and lymphocyte count from 0.5 to 1.0 × 109/L (HR 5.296, 95% CI: 2.082–13.464, P < 0.001) were found to be independent predictors of RP-ILD. These results are presented in Table 3.

Table 3 The discretized serum level of IL-6 and lymphocytes to predict 6-month death and RP-ILD in patients with anti-MDA5-positive DM based on multivariate Cox regression analysis
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Predictive effect of serum level of IL-6 and lymphocyte count on the prognoses of patients with anti-MDA5-positive DM

We investigated the 6-month all-cause mortality and the occurrence of RP-ILD in distinct subgroups based on serum level of IL-6 (log-rank P < 0.001; Fig. 2A and B). Our findings demonstrated that patients with IL-6 ≥ 13.41pg/mL had remarkably higher overall mortality rates compared to those with IL-6 < 13.41pg/mL. Specifically, the 1-month and 3-month mortality rates of patients with IL-6 ≥ 13.41pg/mL were 46.4% and 72.6%, respectively, which were 4.3 times and 3.7 times higher than those with IL-6 < 13.41pg/mL (Supplementary Fig. 3A). Furthermore, the incidence of RP-ILD at 1 month and 3 month was higher in patients with IL-6 ≥ 13.41pg/mL compared to those with IL-6 < 13.41pg/mL (88.1% vs. 33.3%, P < 0.001; 97.6% vs. 41.7%, P < 0.001; Supplementary Fig. 3B).

Fig. 2
figure 2

The Kaplan–Meier survival curves for 6-month all-cause mortality (A) and RP-ILD (B) in patients with anti-MDA5-positive DM among three lymphocyte subgroups; The Kaplan–Meier survival curves for 6-month all-cause mortality (C) and RP-ILD (D) in patients with anti-MDA5-positive DM between two subgroups based on serum level of IL-6

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The Kaplan–Meier survival curves illustrated significant differences in 6-month all-cause mortality and the occurrence of RP-ILD among the three lymphocyte groups (log-rank P < 0.001; Fig. 2C and D). Specifically, the overall mortality rates of patients with lymphocyte count < 0.5 × 109/L, from 0.5 to 1.0 × 109/L, and > 1.0 × 109/L were 28.0%, 21.4% and 1.2%, respectively. Notably, the 1-month mortality rates in the groups with lymphocyte count < 0.5 × 109/L and 0.5 to 1.0 × 109/L were significantly higher than that in the group with lymphocyte count > 1.0 × 109/L (43.3% vs. 26.2% vs. 0, P < 0.001). Similarly, the 3-month mortality rates in the groups with lymphocyte count < 0.5 × 109/L and 0.5 to 1.0 × 109/L were 16.7 times and 9.6 times higher than that in the group with lymphocyte count > 1.0 × 109/L (70.0% vs. 40.5% vs. 4.2%, P < 0.001; Supplementary Fig. 3C). Patients with lymphocyte count < 0.5 × 109/L and 0.5 to 1.0 × 109/L also had a higher incidence of RP-ILD at 1 month and 3 month compared to those with lymphocyte count > 1.0 × 109/L (80.0% vs. 59.5% vs. 16.7%, P < 0.001; 96.7% vs. 64.3% vs. 20.8%, P < 0.001; Supplementary Fig. 3D).

Longitudinal data of lymphocytes contributes to cluster patients with anti-MDA5-positive DM

The current study, consistent with previous findings, revealed that lymphopenia was associated with unfavorable prognosis of anti-MDA5-positive DM. However, previous studies were limited to evaluating peripheral lymphocytes at a single time point. Therefore, we performed GBTM to track the early dynamic changes in peripheral lymphocytes and assess the presence of heterogeneity in individuals allowing for classifications.

Peripheral lymphocytes of 129 patients with anti-MDA5-positive DM were evaluated within the first week after admission. Five models ranging from 1 to 5 trajectory patterns were identified, with three trajectory groups eventually selected based on the requirement of BIC, AvePP and clinical relevance (Fig. 3A). These groups included: Group 1, with low-level of lymphocytes that declined (n = 75, 57.9%); Group 2, with medium-level of lymphocytes that slightly rose (n = 32, 25.2%); and Group 3, with high-level of lymphocytes that rose (n = 22, 16.9%). Additionally, a heatmap illustrating the lymphocytes trajectories in the three groups was plotted (Fig. 3B).

Fig. 3
figure 3

A Three trajectories of lymphocytes in patients with anti-MDA5-positive DM within the first week after admission. B Heatmap of lymphocytes over time for the three trajectory groups. The Kaplan–Meier survival curves for 6-month all-cause mortality (C) and RP-ILD (D) in patients with anti-MDA5-positive DM among the three trajectory groups

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Significant heterogeneity was observed in age of onset, the levels of LDH and serum IL-6 among the three trajectory groups. Patients in group 3 were exposed to more glucocorticoid pulse therapy and biological agents compared to the other two groups. Our data indicated that the 6-month all-cause mortality rates were higher in group 1 (90.7%), lower in group 2 (6.3%), and all patients in group 3 survived. Regarding the incidence of RP-ILD, all patients in group 1 suffered from RP-ILD (100%), followed by group 2 (62.5%) and group 3 (22.7%), as detailed in Table 4. The cumulative risk curves for 6-month all-cause mortality and RP-ILD across the three trajectory groups are presented in Fig. 3C and D. Overall, our findings suggest that patients with initially low-level of lymphocytes exhibited a downward trend with higher mortality and occurrence of RP-ILD.

Table 4 Clinical characteristics of distinct trajectories of lymphocytes in patients with anti-MDA5-positive DM
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Dynamic changes in serum IL-6 among distinct subgroups of patients with anti-MDA5-positive DM

During the first four weeks of follow-up, the level of serum IL-6 in non-survival group was higher than that in survival group, displaying a gradual upward trend. The level of serum IL-6 of survivors remained continuously low level (Supplementary Fig. 4A). Furthermore, the level of serum IL-6 in RP-ILD group was significantly elevated compared to that in non-RP-ILD group at all time point. It changed slightly during the first four weeks, with a drop in the second week. Conversely, patients with non-RP-ILD exhibited persistently low level of serum IL-6 (Supplementary Fig. 4B).

The expression of IL-6 and infiltration of lymphocytes in lung tissues from patients with anti-MDA5-positive DM

To evaluate the role of IL-6 and lymphocytes in the lung injury among patients with anti-MDA5-positive DM, lung specimens from four patients were examined. This included two patients with RP-ILD and two with non-RP-ILD. Microscopically, it showed widened alveolar septa, rupture of alveolar septum or alveolar cavity atrophy, and interstitial fibrous hyperplasia. The histopathological pattern of three cases presented non-specific interstitial pneumonia (NSIP), while one case exhibited organizing pneumonia (OP). The immunohistochemistry of a case with RP-ILD showed increased expression of IL-6 in alveolar epithelium and pulmonary interstitium, while another case showed increased expression of IL-6 in vascular endothelium and alveolar secretions. Furthermore, the infiltration of lymphocytes in lung tissues from patients with RP-ILD was increased compared to those with non-RP-ILD (Fig. 4). Immunofluorescence further showed that the infiltration of CD4 + and CD8 + T cells, particularly CD8 + T cells, was increased in lung tissues from patients with RP-ILD compared to those with non-RP-ILD (Fig. 5).

Fig. 4
figure 4

(A, A’) Case 1 with RP-ILD showed alveolar epithelial hyperplasia, widened alveolar septa, and lymphocytes infiltration. Immunohistochemistry showed increased expression of IL-6 in alveolar epithelium and pulmonary interstitium. (B, B’) Case 2 with RP-ILD showed alveolar metaplasia, interstitial fibrous hyperplasia, and lymphocytes and plasma cells scattered infiltration. Immunohistochemistry showed increased expression of IL-6 in vascular endothelium and alveolar secretions. (C) Case 3 with non-RP-ILD showed atrophy of alveolar cavity and interstitial fibrous hyperplasia, (D) Case 4 with non-RP-ILD showed widened alveolar septa and interstitial fibrous hyperplasia. (C’, D’) Immunohistochemistry showed the expression of IL-6 in Case 3 and 4 was lower compared to Case 1 and 2. (E, E’) H&E stain and immunohistochemistry of normal lung tissues from Case 5 with spontaneous pneumothorax. Original magnification, ×200

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Fig. 5
figure 5

Immunofluorescence showed that the infiltration of CD4 + and CD8 + T cells, particularly CD8 + T cells, was increased in lung tissues from Case 1 (A) and Case 2 (B) with RP-ILD. In contrast, Case 3 (C) and Case 4 (D) with non-RP-ILD, as well as Case 5 (E) and Case 6 (F) with normal lung tissues of spontaneous pneumothorax, showed lower levels of these immune cells. Representative immunofluorescence images of CD4 + T cells (green), CD8 + T cells (red) and DAPI (blue) staining. Scale bar, 50 μm. Original magnification, ×200

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Discussion

This retrospective cohort study shed light on predicting poor outcomes of anti-MDA5-positive DM through increased serum level of IL-6 and lymphopenia. Patients with anti-MDA5-positive DM were classified into subgroups based on serum level of IL-6 and lymphocyte count, revealing distinct prognoses. Tracking the trajectories of lymphocytes during hospitalization facilitated to cluster patients with different outcomes. Pulmonary pathology findings indicated that the expression of IL-6 and infiltration of lymphocytes, characterized by increased CD4 + and CD8 + T cells, in patients with RP-ILD were more significant.

Anti-MDA5-positive DM associated RP-ILD demonstrates striking similarity to lung damage observed in coronavirus disease 2019 (COVID-19), potentially attributed to lymphocytes exhaustion and T cells apoptosis triggered by proinflammatory cytokines [24, 25]. Proinflammatory cytokines, particularly IL-6, have been demonstrated to decrease the cytolytic function of NK cells and CD8 + T cells, resulting in an amplification of pro-inflammatory cytokine cascade. The cytokine storm triggers macrophage activation [26], which is associated with disease activity and severity in anti-MDA5-positive DM [27]. Ferritin, a prominent biomarker of macrophage activation, has been subject to much investigation [3, 13]. A vicious loop was induced by ferritin and pro-inflammatory cytokines, such as IL-6, IL-1β, and IFN-γ. These substances induce activation of NF-κB pathway and initiate an aberrant inflammatory process that ultimately leads to the onset of cytokine release syndrome (CRS) [28]. Therefore, it is noteworthy that macrophage activation may be correlated with the development of CRS, which contributes to the increased serum level of IL-6.

In our study, we sought to broaden our insight into the association between proinflammatory disorders and unfavorable outcomes by measuring levels of 6 serum cytokines. In the analysis of cytokine profiles, we found mixed hypercytokinemia, with higher levels of IL-6 and IL-10 in non-survivors and patients with RP-ILD. However, only IL-6 emerged as an independent predictor of poor prognosis. Interestingly, we observed that the group with low-level of lymphocytes that declined exhibited increased level of serum IL-6. Furthermore, the level of serum IL-6 in non-survivors and patients with RP-ILD remained consistently elevated during the first 4 weeks of follow-up. In line with these findings, a small sample-size study indicated that serum IL-6 ≥ 9pg/mL could serve as a valuable predictor of amyopathic dermatomyositis (CADM) with RP-ILD [29]. IL-6 has been identified as an essential inducer of cell apoptosis [30] and the main contributor to CRS [31]. Overactivation of the type I IFN signaling is a typical “signature” of anti-MDA5-positive DM. Previous studies showed that IL-6 was positively correlated with the type I IFN–regulated chemokines in patients with DM. It suggested potential co-regulation between the type I IFN and IL-6 pathways, indicating a possible regulatory cross-talk between these pathways [32, 33]. Therefore, monitoring the level of serum IL-6 is of great significance for early detection of severe cases.

Tocilizumab, an antagonist of both IL-6 and IL-6 receptor (IL-6R), was reported to be a potential salvage therapy for anti-MDA5-positive DM with refractory RP-ILD in a small sample-size clinical study [34]. In our study, a review was performed involving 17 patients who were treated with tocilizumab, including 5 survivors and 12 non-survivors (Supplementary Table 1). Notably, the non-survivors exhibited increased disease activity, as evidenced by higher levels of serum IL-6, LDH, and ferritin, lower oxygenation index, and a shorter course of disease. Eight out of the 12 non-survivors were administered tocilizumab within one week of diagnosis, while 3 non-survivors were prescribed from 7 to 10 days after diagnosis. The established recommendation of tocilizumab for treating CRS is 8 mg/kg, administered once every 4 weeks. However, in our cohort, 9 out of the 12 non-survivors were given an inadequate dosage. Further analysis of the serum levels of IL-6 before and after treatment with tocilizumab showed that most of the non-survivors showed an upward trend in IL-6. Despite its success in treating some critical patients with anti-MDA5-positive DM, IL-6 blockade alone may be insufficient to control the inflammatory cascade. Tofacitinib, a Janus kinase inhibitor that targets JAK1 and JAK3, inhibits the phosphorylation of STAT5, STAT1, and STAT3 in response to IL-6 exposure [35]. Our study also revealed a relationship between the administration of tofacitinib and unfavorable prognosis, which was attributed to increased disease activity and amplification of inflammatory cascade (Supplementary Table 2). A previous clinical trial indicated that tofacitinib could be a promising therapy in the early stage of disease, prior to severe deterioration of pulmonary function [36]. An observational study suggested that tofacitinib may have a potential effect on improving the outcomes of anti-MDA5-positive with ILD. However, the 6-month and 1-year mortality rates of patients receiving tofacitinib were high due to a great proportion of the enrolled patients with RP-ILD [37].

Consistent with previous studies, our finding indicates lymphopenia is a powerful predictor of mortality and RP-ILD in patients with anti-MDA5-positive DM. In a large-scale Chinese cohort study, patients were categorized into three distinct subgroups based on their peripheral lymphocyte count: normal lymphocyte group (≥ 1100cells/µl), mild lymphopenia group (≥ 550 cells/µl and < 1100 cells/µl), and severe lymphopenia group (< 550 cells/µl). The results revealed that individuals in the severe lymphopenia group had higher 3-month and 6-month mortality rates compared to the other two groups. Additionally, the study defined three clinical phenotypes using unsupervised machine learning analysis and found the RP-ILD cluster presented severe lymphopenia and fatal prognosis [9]. A detailed feature of lymphopenia is notable decrease in peripheral T cells. Recent studies reported that decreased CD4 + T cells and CD8 + T cells were associated with pulmonary interstitial lesions and the development of RP-ILD [38, 39]. Previous studies found that the decreased CD8 + T cells were regarded as a valuable predictor of mortality in anti-MDA5-positive DM and ILD, as well as in all patients with DM and ILD [40]. Type I IFN signaling directly affected lymphocyte recirculation and caused lymphopenia [41]. The elevated type I IFN signaling was found to influence the differentiation and function of CD8 + T cells in patients with active juvenile DM, leading to decreased CD8 + T-cell ratio in the periphery [42]. In the lungs of patients with active anti-MDA5-positive DM, increased proportions of interferon stimulating gene+ (ISG+) CD4 + cells, ISG + CD8 + cells and proliferating CD8 + T cells were observed, accompanied with overactivation of the type I IFN signaling [43]. Further investigation is warranted to explore the molecular mechanism by which type I IFN signaling affects lymphopenia and infiltration of T cells in the lungs.

The study tracked changes in peripheral lymphocytes during the first week after admission and established three trajectory groups based on GBTM. Peripheral lymphocytes were monitored within the first week due to a certain percentage of patients either discharged or died between 7 and 10 days after admission, with approximately three quarters of patients undergoing a complete blood count. The findings revealed that the trajectory group with low-level of lymphocytes that declined had the highest rate of death and RP-ILD. On the contrary, the other two trajectory groups with medium and high levels of lymphocytes experienced a return by day 7 and manifested more favorable prognosis. In a recent study, lymphocyte count was monitored for the first 4 weeks after admission. The average lymphocyte counts per week during the first month in the non-survival group showed a sustained decrease. The study elucidated that a lower lymphocyte count (< 0.61 × 109/L) in the first 2 weeks could predict 6-month all-cause mortality [44]. The lymphocytes were positively correlated with the pulmonary interstitial lesions. After treatment with prednisolone and immunosuppressants, patients experiencing exacerbation of pulmonary interstitial lesions manifested decreased lymphocytes [38]. In summary, our study, in line with previous research, confirms that monitoring the continuous and dynamic changes in lymphocytes during hospitalization can help identify the progression and deterioration of disease.

Histologically, patients with ILD presented two patterns: NSIP and OP, which is consistent with previous findings [45]. The lung biopsy of case 1 was performed during the early stage of disease, while the lung biopsy of case 2 was performed 2 weeks after onset. We observed sporadic lymphocytes infiltration in the pulmonary interstitium of patients with RP-ILD. Furthermore, an increased infiltration of CD4 + and CD8 + T cells, particularly CD8 + T cells, was observed in lung tissues from patients with RP-ILD. The lymphopenia observed in patients with RP-ILD, characterized by decreased CD4 + and CD8 + T cells, may be attributed to the migration of lymphocytes to the lungs to take part in the local immune response. Additionally, we found overexpression of IL-6 in the alveolar and pulmonary interstitium in one case with RP-ILD, and overexpression of IL-6 in the vascular endothelium and alveolar secretions in the other case with RP-ILD. Furthermore, the level of serum IL-6 in both two cases was significantly elevated. In the MDA5-immunized mice model, upregulation of IL-6 mRNA was observed in the lung, with the anti-IL-6R antibody alleviating histopathological features of ILD [46]. Previous studies have confirmed IL-6 drives pulmonary inflammatory response and fibrogenesis [47], as well as polarizes activation of profibrotic macrophages [48] and inhibits apoptosis of fibroblasts [49]. Excessive IL-6 accounts for the pulmonary tissue damage of anti-MDA5-positive DM. The various ISGs in over-stimulated type I interferon signaling were highly expressed in lung tissue [50]. Intriguingly, a study on autopsy lung samples from COVID-19 proposed that a pattern of high local expression of ISGs showed increased cytokines and weak immune cell infiltration, indicating an early innate stage of the disease. Conversely, a pattern of low expression of ISGs showed excessive immune cell infiltration, particularly activated CD8 + T cells and macrophages, along with decreased innate cytokines, representing a later stage of the disease [51]. Accumulating evidence on the pathological features of anti-MDA5-positive DM with ILD is essential to elucidate potential similarities in disease progression between anti-MDA5-positive DM and COVID-19.

The multivariate Cox regression analysis revealed older age and elevated level of LDH were associated with disease severity and prognosis. As previously reported, the risk of 6-month mortality was found to be higher in male patients over 54 years old [52]. Moreover, patients aged over 60 years showed poor responses to combination immunosuppressive therapy and had unfavorable prognosis [53]. Several studies have highlighted LDH, a cytoplasmic enzyme associated with cell damage or death, as a predictive biomarker for mortality and RP-ILD [54]. LDH has been recognized as an indicator of macrophage activation [55]. Activated macrophages promote pro-inflmmatory and pro-fibrogenic response in ILD [56], contributing to the pathogenesis of anti-MDA5-positive DM.

Several studies have investigated time-dependent changes in RP-ILD and mortality among anti-MDA5-positive DM, suggesting that the initial six months after disease onset are a crucial period with poor prognosis. Our data showed that 84.3% of RP-ILD and 54.5% of mortality occurred within the first month of diagnosis, and over 90% of both RP-ILD and mortality happening within the first 3 months. The short-term poor prognosis in severe patients indicates rapid progression or exacerbation of the disease. Beyond 3 months after diagnosis, disease progression appeared to settle down and the tendency persisted until the end of follow-up. Notably, the time-window for unfavorable outcomes observed in our study was earlier than previous findings, likely due to the enrollment of considerable critically ill patients. Taken together, monitoring the disease course and implementing early efficient strategies for high-risk patients within the first 3 months may improve the prognosis.

Our research had several limitations. Firstly, as a retrospective observational study, it is limited to the inherent nature. Secondly, some meaningful markers, such as ferritin and KL-6, were not reported due to inconsistent measures across two centers or more than 30% missing values. Thirdly, a significant number of critical patients were enrolled in the study, potentially leading to selection bias. Fourthly, although medical interventions had specific effects on outcomes, they were not further explored as potential risk factors due to heterogeneity in treatment practices across different centers. Fifthly, histopathological observations were limited due to the invasive nature of lung biopsies and the risk of exacerbating the primary disease.

In conclusion, our study demonstrated that increased serum level of IL-6 (≥ 13.41pg/mL) and severe lymphopenia were promising predictors of 6-month all-cause mortality and the occurrence of RP-ILD in anti-MDA5-positive DM patients. Additionally, tracking distinct trajectories of lymphocytes during hospitalization can be utilized to cluster patients.

Data availability

All data generated or analyzed during this study are included in the article and supplementary material. Further inquiries can be directed to the corresponding authors.

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Acknowledgements

We acknowledge the contribution of Dr. Shuo Yang to statistical analysis. He was a statistician from the Department of Epidemiology and Biostatistics, School of Public Health; Sun Yat-Sen University, Guangzhou, China.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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  1. Yuanyuan Niu, Suling Liu and Qian Qiu these authors contributed equally.

Authors and Affiliations

  1. Department of General Practice, the First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, Guangdong Province, 510080, China

    Yuanyuan Niu

  2. Department of Rheumatology and Immunology, the First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, Guangdong Province, 510080, China

    Suling Liu, Qian Qiu, Youjun Xiao, Liuqin Liang & Hanshi Xu

  3. Department of Rheumatology and Immunology, the First Affiliated Hospital of Guangzhou Medical University, No. 151 Yanjiang West Road, Guangzhou, Guangdong Province, 510120, China

    Di Fu & Shanhui Ye

  4. Department of Rheumatology and Immunology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, No. 106 Zhongshan Er Road, Guangzhou, Guangdong Province, 510180, China

    Yang Cui

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Contributions

Yuanyuan Niu, Suling Liu and Qian Qiu contributed equally. Conceptualization: Yuanyuan Niu and Hanshi Xu; methodology: Suling Liu and Di Fu; formal analysis and investigation: Yuanyuan Niu, Qian Qiu, Youjun Xiao and Liuqin Liang; writing–original draft preparation: Yuanyuan Niu; writing–review and editing: Yang Cui, Shanhui Ye and Hanshi Xu; supervision: Hanshi Xu. All authors reviewed the manuscript.

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Niu, Y., Liu, S., Qiu, Q. et al. Increased serum level of IL-6 predicts poor prognosis in anti-MDA5-positive dermatomyositis with rapidly progressive interstitial lung disease. Arthritis Res Ther 26, 184 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13075-024-03415-5

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13075-024-03415-5

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Arthritis Research & Therapy

ISSN: 1478-6362

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