Investigating the Profile of Patients with Idiopathic Inflammatory Myopathies in the Post-COVID-19 Period: Emphasizing Myocardial Injury

doi:10.21203/rs.3.rs-4886868/v1

Introduction: The 2019 coronavirus disease (COVID-19) pandemic has changed the characteristics of many diseases. It remains unclear whether idiopathic inflammatory myopathies (IIMs) exhibit distinct phenotypes in the context of COVID-19.

Methods: This retrospective study included 171 IIMs patients with a history of COVID-19 (prior COVID-19, PC) and 121 without (no-prior COVID-19, NPC). Medical histories, lab tests, and echocardiography data were compared.

Results: PC group exhibited a greater incidence of cardiac damage, including a greater proportion of clinical diagnosis of myocarditis (p=0.02), palpitation (p=0.031), and MYOACT/MITAX cardiovascular involvement scores (all p＜0.001), and elevated levels of myoglobin (MYO, p=0.03), creatinine kinase MB (CK-MB, p=0.015), cardiac troponin T (cTnT, p=0.011), N-terminal pro-B-type natriuretic peptide (NT-proBNP, p=0.028), lactate dehydrogenase (LDH, p=0.033), and hydroxybutyrate de-hydrogenase (HBDH, p=0.019). Echocardiographic analysis revealed greater diameter of left atrium (LA, p=0.040), left ventricle (LV, p=0.013), greater thicknesses of interventricular septum (IVS, p=0.043), and greater end-diastolic volume (EDV, p=0.036) in the PC group than in the NPC group. Transcriptional data analysis based on public databases indicated that various mechanisms, including collagen matrix proliferation, calcium ion pathway regulation, oxidative stress, cell proliferation, and inflammatory molecules, collectively contribute to the pathogenesis of myocardial damage in patients with IIMs and COVID-19.

Conclusion: The study serves as a crucial reminder for clinicians to remain vigilant regarding the enduring cardiovascular consequences associated with IIMs subsequent to COVID-19.

post-COVID-19

COVID-19

SARS-CoV-2

idiopathic inflammatory myopathies (IIMs)

myocardial damage

With the implementation of effective control measures for the 2019 coronavirus disease (COVID-19), the impact of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is gradually diminishing. However, a large body of research shows that at least 10% of people with acute SARS-CoV-2 infection continue to experience long-term symptoms after initial recovery, and these conditions are referred to as long COVID or post-acute sequelae of COVID-19 [1]. Long COVID can involve multiple organ systems, including respiratory system dysfunction, cardiovascular complications, central nervous system dysfunction, and blood clotting dysfunction [1].

Autoimmunity is one of the most important hypothesized mechanisms of long COVID. Various autoantibodies, including anti-nuclear antibodies (ANAs), lupus anticoagulants, anti-2-glycoprotein 1β, and anti-cardiolipin antibodies, have been identified in COVID-19 patients [2]. A plethora of reports on autoimmune thrombocytopenic purpura, autoimmune hemolytic anemia, inflammatory arthritis, and vasculitis following COVID-19 further substantiate the potential association between COVID-19 and autoimmune diseases [2, 3].

IIMs are a group of systemic autoimmune inflammatory diseases that mainly involve the proximal muscles of the extremities [4]. Various viral infections, such as coxsackie B, parvovirus, enterovirus, human T-cell-lymphotropic virus (HTLV-1), and human immunodeficiency virus (HIV), have been recognized as significant environmental factors in the development of IIMs [2]. Following SARS-CoV-2 infection, patients frequently experience symptoms such as myalgia, myasthenia, and elevated creatine kinase levels, and even new-onset IIMs have been reported [3]. Although two studies have reported some characteristics of IIMs during the COVID-19 pandemic [5, 6], the small sample sizes of these studies make it difficult to determine whether COVID-19 has altered the clinical manifestations of IIMs. Our study involved 292 patients with IIMs, aimed at comprehensively summarizing the clinical features, laboratory findings, and imaging data, and provided valuable insights into the characteristics of IIMs patients in the post-COVID-19 period.

2.1 Research design and subjects

In this retrospective study, we recruited all IIMs patients who were admitted to West China Hospital between January 2022 and December 2023. All participants were aged 18 years or older and met the 2017 EULAR/ACR criteria for the classification of IIMs [7]. Moreover, patients with other connective tissue diseases, malignancies, inherited myogenic disorders, tuberculosis, septi-copyemia, the acute phase of COVID-19, and those with missing data on myocardial markers were excluded. Finally, 292 IIMs patients who met the inclusion criteria were included in the study cohort. Patients were divided into two groups according to whether they had a history of COVID-19: no-prior COVID-19(NPC, n = 121) and prior COVID-19 (PC, n = 171). Prior COVID-19 was defined as patients had symptoms of viral infection such as fever, myalgia, sore throat, cough, positive SARS-CoV-2 nucleic acid, and the SARS-CoV-2 nucleic acid turned negative for at least 4 weeks after treatment or no treatment. The evaluation and inclusion process for these patients is illustrated in Fig. 1. The study was approved by the ethical committee of West China Hospital of Sichuan University (No. 695 in 2020).

2.2 Collection of clinical features

All the data were collected from the electronic medical records database of West China Hospital. The medical data collected included demographic characteristics, such as age, gender, duration of IIMs, duration of COVID-19, clinical symptoms and signs, including fever, cough, expectoration, dyspnea, arthritis, myalgia, myasthenia, and rash, and laboratory features, including routine blood parameters, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, alkaline phosphatase (ALP) level, gamma glutamyltransferase (GGT), creatine kinase (CK) level, lactate dehydrogenase (LDH) level, hydroxybutyrate dehydrogenase (HBDH) level, myoglobin protein (MYO) level, cardiac troponin T (cTnT) level, N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, creatine kinase isoenzyme MB (CK-MB) level, triglyceride level, cholesterol level, fibrinogen level, antithrombin III activity, antinuclear antibodies (ANA), anti-Ro52 antibody, myositis specific antibodies, and echocardiographic parameters.

2.3 Myositis Disease Activity Assessment

Disease activity scores were performed by two experienced rheumatologists based on medical records. Disease activity for IIMs was measured using Myositis Activity Assessment Visual Analog Scales (MYOACT) and the Myositis Intention-to-treat Activity Index (MITAX), which were established by the International Myositis Assessment and Clinical Studies (IMACS) group. The detailed scoring methods can be found in our previous article [8].

2.4 Analysis of Differentially Expressed Genes

We retrieved the COVID-19 patient dataset (GEO accession ID: GSE151879), which used the high-throughput sequencing Illumina NextSeq 500 platform to detect RNA sequences, from which we sorted the myocardial tissue samples from 3 COVID-19 patients and 3 normal people [9]. The DM patient dataset (GEO accession ID: GSE143323), including muscle samples from 39 DM patients and 20 healthy controls, was extracted from RNA sequences using the high-throughput sequencing Illumina HiSeq 3000 platform[10]. Using R software 2 the "DESeq2" and the "edgeR" packages, COVID-19 dataset (GSE151879) and DM dataset (GSE143323), to |Log2 Fold Change| > 0.585 and | adj.P.Val. A value of | < 0.05 was used as the implementation standard to find the differentially expressed genes (DEGs) of the two datasets, and the "Venn" package in R software (4.2.1) was used to identify the common DEGs that were differentially expressed and upregulated or downregulated in the two datasets at the same time. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed on DEGs using the enrichment database to reveal the functions of DEGs. The "clusterProfiler" package in R software (4.2.1) was used to screen the common DEGs of potential biological functions and physiological pathways. GO terms included three parts: biological process (BP), cellular component (CC) and molecular function (MF). A P value < 0.05 and q-value < 0.25 were used as standardized indices.

2.5 Statistical analysis

SigmaPlot 12.5 and/or GraphPad Prism 8.0.2 software were used for data analysis. Continuous variables are presented as the mean ± standard deviation (M ± SD) or median (Q25, Q75) depending on whether they fit a normal distribution. Categorical variables are described statistically using percentages. When the normality (Shapiro–Wilk) test was passed, an independent-samples t test and one-way ANOVA were conducted for two-group or multiple comparisons, respectively; otherwise, the Mann–Whitney U test was used for comparison. Chi-square tests were used to compare categorical variables. All tests were bilateral, and p < 0.05 was considered to indicate statistical significance.

3.1 Baseline demographics

The demographics and clinical characteristics of the patients are presented in Table 1. As observed, the general baseline characteristics, including age, sex, BMI, and duration of IIMs, were comparable between two groups (Table 1). The proportions of patients with newly IIMs were 84 (69.42%) and 109 (63.74%) in the NPC and PC groups, respectively, showing no significant difference (p>0.050). In the PC group, the time elapsed from prior SARS-CoV-2 infection ranged from 4 weeks to 11 months (data not shown), with an average duration of 5.92±3.18 months. There were no statistically significant differences in comorbidity incidence or treatment between the two groups (p>0.050).

3.2 Effects of COVID-19 on the clinical characteristics of patients with IIMs

We analyzed the clinical symptoms of patients with IIMs and observed that the PC group exhibited a greater prevalence of cardiopulmonary symptoms than did the NPC group (Table 1). These symptoms included palpitation (21.05% vs. 10.74%, p=0.031) and respiratory rate (20.56±2.10 vs. 20.04±0.98, p=0.048). The proportion of patients with dyspnea showed a slight increasing trend in the PC group (67.25% vs. 57.85%). No significant difference was found in heart rate between the two groups. The NPC group had more rashes (69.42% vs. 52.05%, p=0.004) and arthritis/ arthralgia (40.50% vs. 26.9%, p=0.021) than did the PC group. Furthermore, disease activity was assessed in both groups (Table 1). Compared to those in NPC group, patients in the PC group had greater global MYOACT/MITAX scores (0.37±0.12 vs. 0.35±0.11, p=0.046; 0.29(0.21,0.40) vs. 0.27(0.18,0.35), p=0.043), MYOACT/MITAX cardiovascular involvement scores (6 (0, 7) vs. 0 (0, 6), p＜0.001; 9(0, 9) vs. 0 (0, 9), p＜0.001), and MYOACT pulmonary involvement scores (4.97±3.37 vs.4.27±3.35, p=0.033). The MYOACT/MITAX cutaneous involvement scores in the NPC group were greater than those in the PC group (6 (0, 7) vs. 5 (0, 7), p=0.035; 3 (0, 3) vs. 1 (0, 3), p=0.027). The proportion of patients with clinically diagnosed myocarditis in the PC group was significantly greater than that in the NPC group (12.87% vs. 4.13%, p=0.020). The median time from COVID-19 to the diagnosis of myocarditis was 6 (3,9) months (data not shown in the paper).

Subsequently, we analyzed of the laboratory characteristics of the two groups, as presented in Table 2. The ratio of anti-aminoacyl transfer RNA synthetase antibody (ARS) in the PC group was greater than those in the NPC group (24.56% vs. 11.57%, p=0.009). There were no significant differences in the rates of positivity for antimelanoma differentiation associated gene 5 antibody (MDA5), antinuclear matrix protein 2 antibody (NXP2), anti-helicase protein antibody (Mi2), anti-small ubiquitin-like modifier activating enzyme (SAE), anti-transcription intermediary factor 1γ(TIF1γ), anti-3-hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR), anti-signal recognition particle (SRP), or ANA between the two groups. The percentage of patients who were positive for anti-Ro52 antibody in the PC group was greater than that in the NPC group (49.69% vs. 36.98%, p=0.046). However, markers of myocardial injury, such as MYO(128.50(26.70, 620.25) vs. 53.25(21.82, 462.50), p=0.030), CK-MB(7.32(1.64, 70.50) vs. 3.04(1.18, 21.52), p=0.015), cTnT(54.50(15.90, 153.00) vs. 22.00(9.65, 101.35), p=0.011), NT-proBNP(133.00(61.50,322.50) vs. 97.50(41.75, 232.50), p=0.028), LDH (360.00(250.00, 590.00) vs. 316.00(234.50, 488.50), p=0.033), HBDH (274.00(194.00, 429.00) vs. 231.00(176.00, 366.00), p=0.019), were significantly greater in the PC group than in the NPC group. Additionally, GGT levels were significantly greater in the PC group (41.00(19.00, 98.00) vs. 28.00(18.00, 60.50), p=0.048). Interestingly, the fibrinogen levels (2.67(2.21,3.38) vs. 3.03(2.40,4.08), p=0.002) and platelet counts (198.00(157.00,246.00) vs. 219.00(174.50,261.50), p=0.014) in the PC group were significantly lower than those in the PC group. In addition, the white blood cell and neutrophil counts in the PC group were significantly greater than those in the NPC group (7.44(5.48, 9.75) vs. 6.40(4.46, 9.11), p=0.018; 5.30(3.76, 7.18) vs. 4.39(2.89, 7.27), p=0.023). Conversely, the levels of CK, ALT, AST, ALP, blood creatinine, triglyceride, cholestero, AT-III activity, CRP, hemoglobin, and lymphocyte counts were not significantly different between these two groups (Table 2). These findings suggest that patients with IIMs who have previously contracted COVID-19 display altered clinical symptoms and laboratory test results, particularly pertaining to cardiac characteristics.

3.3 Echocardiographic parameters exhibited alterations in IIMs patients with a history of COVID-19

To further investigate the impact of COVID-19 on cardiac function in patients with idiopathic inflammatory myopathies (IIMs), we analyzed echocardiography parameters, including measures of cardiac structure and function (Table 3). Due to missing echocardiography data, there were 111 and 149 patients in the no prior COVID-19 (NPC) and prior COVID-19 (PC) groups, respectively. Cardiac structural parameters revealed that the left atrial diameter (LA) and left ventricular diameter (LV) were greater in the PC group than in the NPC group (46.43±3.68 vs. 45.52±3.25, p=0.040; 33.00(30.00, 36.00) vs. 31(28.00, 34.00), p=0.013), as well the interventricular septum (IVS, (10.00(9.00, 11.00) vs. 9.00 (8.00, 10.00), p=0.043) and left-ventricular posterior wall (LVPW, 8.88±1.13 vs. 8.56±0.84, p=0.042). The end-diastolic volume (EDV) was higher in the PC group than in the NPC group (99.49±18.73 vs. 94.81±15.76, p=0.036), while the end-diastolic dimension (EDD) was greater in the PC group than in the NPC group (47.00(44.00, 49.00) vs. 45.00(44.00, 48.00), p=0.057). No significant differences were observed for the other echocardiographic parameters examined. In addition, we analyzed the electrocardiograph (ECG) characteristics of patients with IIMs, and there was no statistically significant difference in the rate of arrhythmia between the two groups (Supplementary Table 1). The characteristics associated with cardiac damage in all IIMs patients are summarized in Figure 2.

To ascertain the potential association between the extent of cardiac damage in individuals with post-COVID-19 IIMs and the duration elapsed since SARS-CoV-2 infection. Patients with IIMs were classified according to the time since previous SARS-CoV-2 infection. Supplemental Table 2 showed that IIMs patients with a short period of acute COVID-19 had a higher MYOACT/MITAX global score and the highest MYOACT pulmonary score (all p<0.05), while there were no statistically significant differences in cardiac damage related indicators.

3.4 The putative mechanism underlying COVID-19-induced cardiac damage in patients with IIMs

To investigate the potential mechanism of cardiac injury in patients with IIMs in the post-COVID-19 era, we employed RNA-seq technology coupled with bioinformatics analysis to elucidate disparities in gene expression profiles between dermatomyositis (DM) patients and COVID-19 patients. By examining the number of DEGs between DM patients and COVID-19 patients, we identified 7189 DEGs in DM patients (Figure 3A), comprising 5654 upregulated genes (depicted as red dots) and 1679 downregulated genes (depicted as blue dots). Conversely, COVID-19 patients exhibited 3080 DEGs (Figure 3B), including 1278 upregulated genes (red dots) and 1802 downregulated genes (blue dots). A comparison of DEGs between DM patients and COVID-19 patients revealed an overlap of 720 genes (Figure 3C). To explore the underlying mechanisms and pathways associated with these DEGs within our datasets, functional enrichment analyses using Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes were performed. The results demonstrated that biological processes and enriched pathways related to collagen matrix proliferation, calcium ion pathway regulation, oxidative stress response, cell proliferation, and cell inflammatory molecules were significantly enriched among these targets (Figure 3D).

The COVID-19 pandemic has changed the patterns and characteristics of many diseases, including diabetes and cardiovascular disease [11–13]. A mounting body of research has focused on elucidating the association between COVID-19 and autoimmune diseases [2, 3]. Unfortunately, few studies have provided a detailed description of the characteristics of IIMs presentation in post-COVID-19 patients. This retrospective study aimed to delineate IIMs in the context of the post-COVID-19 period, with a specific focus on identifying significant alterations in these patients, especially with respect to cardiac damage.

Our study revealed that myocardial damage, including increased incidence of palpitations, increased heart disease activity score, increased myocardial marker levels, and deterioration of cardiac structure as indicated by echocardiography, was the most prominent manifestation of post-COVID-19 infection in IIMs patients, as did the number of IIMs with a clinical diagnosis of myocarditis. Cardiac damage is an important complication of IIMs, and affects the mortality of IIMs patients [14]. In fact, the cardiac involvement of IIMs patients is relatively insidious, and most patients often have no clinical symptoms, only elevated myocardial enzymes, cardiac magnetic resonance imaging (MRI) and/or myocardial biopsy abnormalities, known as subclinical cardiac involvement [14]. The reported proportion of patients with IIMs with cardiac damage ranges from 9 to 72% [15]. The cardiovascular effects of the evolution of SARS-CoV-2 infection are among the most prominent and urgent concerns [16]. According to a multicenter prospective study of patients with myocardial damage during COVID-19, myocardial damage occurs in one third of patients with COVID-19 and is associated with an increased risk of death [17]. Even myocardial damage can persist until the recovery period [18]. The American College of Cardiology has provided detailed explanations and recommendations for adults with cardiovascular sequelae post-COVID-19 [19]. However, few studies have focused on cardiac damage in patients with post-COVID-19 IIMs. Previous studies have indicated that the concurrent presence of myositis and inflammatory cardiac disease in COVID-19 patients is characterized by a younger age group and fewer respiratory symptoms [20, 21]. In individuals with newly diagnosed ASS following SARS-CoV-2 infection, clinical manifestations solely involve myocardial and skeletal muscle involvement [22]. More interestingly, no significant difference was found in respiratory or skeletal muscle damage between the two groups in our study. These results indicate that SARS-CoV-2 has the potential to alter long-term trajectories associated with cardiac suffering among individuals affected by IIMs.

There are many hypotheses about the mechanism of cardiac damage caused by SARS-CoV-2, including SARS-CoV-2 directly attacking myocardial cells or endothelial cells, SARS-CoV-2 infection triggering cytokine storms caused by immune dysregulation, and hypercoagulable state leading to cardiac damage [23–25]. Myocardial injury after SARS-CoV-2 infection was associated with cytokines in peripheral blood in a large retrospective study, myocarditis was identified in autopsy studies, and microthrombi were identified on cardiac MRI in patients who recovered from COVID-19[26–28]. Interestingly, our data showed that platelet and fibrinogen levels were lower in patients with IIMs during the post-COVID-19 period, which may suggest that abnormal coagulation is the mechanism of myocardial damage in patients with IIMs. Our findings have been confirmed in other studies of long COVID patients. Martins-Goncalves investigated platelet function in post-COVID-19 recovery patients and discovered persistent platelet activation and hyperactivity compared to healthy controls [29]. An 18-month follow-up study on peripheral blood clotting status among individuals recovering from COVID-19 revealed an enduring procoagulant state associated with persistent symptoms [30]. Complement system activation is an important mechanism of coagulation abnormalities [31].

To further investigate the potential mechanisms of myocardial injury in patients with IIMs during the post-COVID-19 period, we employed transcriptomics and bioinformatics analysis. The enrichment analysis of DEGs revealed that collagen matrix proliferation, calcium ion pathway regulation, oxidative stress, cell proliferation, and inflammatory molecules were key factors contributing to cardiac damage in IIMs patients infected with SARS-CoV-2. Our bioinformatics analysis results are consistent with the hypothesized mechanisms underlying COVID-19-associated heart injury. The persistence of the virus in cardiac tissue triggers inflammation leading to myocardial fibrosis; alternatively, viral-induced changes in host proteins can cross-react via molecular mimicry mechanisms [16]. A study investigating postmortem examinations of COVID-19 fatalities reported widespread muscle and myocardial damage despite low or negative viral loads in tissues, suggesting a possible role for immune-mediated myocardial injury [32]. In conclusion, cardiac injury following SARS-CoV-2 infection is likely multifactorial; therefore, a comprehensive understanding of these mechanisms is crucial for improving diagnosis and treatment processes. Further clinical and basic research efforts are urgently needed to explore this topic.

In addition, our data present several additional features of IIMs in the post-COVID-19 period. The proportion of serum ARS is significantly increased in IIMs patients. At present, it is generally believed that the serum antibodies of IIMs patients are closely related to clinical subtype, so we analyzed the subtype composition of IIMs (Supplementary Table 3). We found structural changes in the IIMs subtypes after SARS-CoV-2 infection, with a lower proportion of patients with dermatomyositis and anti-MDA5-positive dermatomyositis, a greater proportion of patients with ASS and unclassified IIMs. Case reports have documented the emergence of IIMs following the COVID-19 pandemic [3, 22, 33]. Most importantly, COVID-19 and anti-MDA5 positive dermatomyositis have notable similarities in clinical features and pathogenesis, including comparable pulmonary interstitial lesions, activation of the IFN-I signaling pathway, and response to immunosuppressive therapy [34, 35]. These findings suggest that SARS-CoV-2 may serve as an environmental risk factor for the onset of IIMs [36]. Previous studies have reported that the proportion of COVID-19 patients who are anti-MDA5 antibody positive is increased, and it is a marker of severe disease and poor prognosis [37]. However, we found that the proportion of post-COVID-19 patients with anti-MDA5 positive dermatomyositis did not increase. This suggests that not all patients with COVID-19 who are positive for anti-MDA5 antibodies are diagnosed with dermatomyositis and that the mechanisms underlying the two diseases are potentially different. In addition, this result may also be due to survivor bias. The increased incidence and hospitalization rate of antisynthetase syndrome in post-COVID-19 patients have also been reported in other studies, but the specific mechanism is still unclear [38, 39].

Elevated bile duct enzymes are another feature of patients with IIMs in the post-COVID-19 period. Increased expression of angiotensin-converting enzyme 2 (ACE2) in the biliary epithelium, increases susceptibility susceptible to SARS-CoV-2 infection, leading to chronic liver disease and providing insights into the potential molecular mechanism underlying biliary tract damage caused by COVID-19 [40, 41]. Roth et al. characterized liver biopsies from three individuals who experienced cholestasis after recovering from COVID-19 and concluded that post-COVID-19 cholangiopathy represents a distinct form of liver injury [41]. Patients with IIMs in the post-COVID-19 period show increased white blood cell and neutrophil counts, while there was no significant difference in the dosage of glucocorticoids. This phenomenon has been mentioned in other studies of long COVID [42, 43]. The specific mechanism is not clear and may be related to the chronic inflammatory state and stress state of patients. However, further prospective studies are needed to explore the pathogenesis and clinical outcomes of IIMs in this context.

Our study also has several limitations. First, this was a retrospective study conducted at a single center, and all the data were obtained from the electronic medical records database. Detailed information regarding the COVID-19 status of these patients was not available, preventing us from determining any potential associations with subsequent cardiac injury. Second, more specific detection methods, such as cardiac MRI and myocardial biopsy, are required to accurately assess cardiac damage in these patients. In addition, the absence of other connective tissue diseases and healthy volunteer controls in this study does not confirm that myocardial damage is specific in patients with IIMs. Last, more than anything, it remains unclear whether the mechanism of disease evolution of IIMs after the COVID-19 pandemic differs fundamentally from that before the outbreak.

The clinical manifestations of patients with IIMs following COVID-19 exhibit notable alterations, particularly in terms of cardiac impairment. Our findings serve as a crucial reminder for clinicians to remain vigilant regarding the enduring cardiovascular consequences associated with IIMs subsequent to COVID-19.

Ethics statement

The study was approved by the ethical committee of West China Hospital of Sichuan University (No. 695 in 2020). Informed consent was obtained from all subjectsAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Funding

This work was supported by the Sichuan Science and Technology Program (2020YFS0005) and the International Cooperation Program of Science and Technology Department of Sichuan Province(2023YFH0081).

Financial disclosure

The authors have no financial relationships relevant to this article.

CRediT authorship contribution statement

Lu Cheng: Writing – review & editing, Writing – original, draft, Visualization, Validation. Yan-Hong Li: Writing – original draft, Formal analysis. Yin-Lan Wu: Methodology, Formal analysis, Data curation. Yu-Bin Luo: Supervision, Conceptualization. Yu Zhou: Resources. Tong Ye: Data curation. Xiu-Ping Liang: Investigation. Tong Wu: Investigation. De-Ying Huang: Investigation. Jing Zhao: Investigation. Yi Liu: Project administration. Zong-An Lang: Supervision, Funding acquisition, Conceptualization. Chun-Yu Tan: Supervision, Funding acquisition, Conceptualization.

Consent to participate

Written informed consent was obtained from all individual participants were included in the study.

Consent for publication

The authors affirm that human research participants provided informed consent for publication.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Declaration of competing interest

The authors have no conflicts of interest relevant to this article.

Acknowledgments

We would like to thank AJE organization for the English language editing.

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Table 1. Baseline characteristics of IIMs patients

Characteristic	No prior COVID-19 (NPC, n=121)	Prior COVID-19 (PC, n=171)	p
Female sex, n(%)	95 (79.24)	126(73.68)	0.329
BMI (kg/m²)^§	22.22(19.83,24.59)	22.48(20.44,25.00)	0.331
Age (years)	51.00(45.40,57.05)	52.00(44.00,58.00)	0.472
First diagnosed IIMs, n(%)	84 (69.42)	109(63.74)	0.377
Disease duration (months)	6.00(3.00,24.00)	10.00(3.00,24.00)	0.489
Time since prior COVID-19 (months)^#	-	5.92±3.18	-
Comorbidities
Hypertension, n(%)	11(9.09)	20(11.70)	0.604
Diabetes, n(%)	16(13.22)	21(12.28)	0.952
Coronary artery disease, n(%)	5(4.13)	8(4.68)	0.948
Hyperlipidaemia, n(%)	33(27.27)	37(21.64)	0.331
Cerebral infarction, n(%)	1(0.83)	0	-
COPD, n(%)	2(1.65)	2(1.17)	0.872
Interstitial lung disease, n(%)	70(57.85)	101(59.06)	0.931
Chronic kidney disease, n(%)	1(0.83)	2(1.17)	0.762
Chronic liver disease, n(%)	3(2.48)	9(5.26)	0.378
Anemia, n(%)	24(19.84)	23(13.45)	0.193
Disease activity evaluation
MTOACT constitutional (score)	6(6, 7)	7(6, 7)	0.138
MYOACT cutaneous (score)	6(0, 7)	5(0, 7)	0.035*
MYOACT skeletal (score)	0(0, 5)	0(0, 0)	0.244
MYOACT gastrointestinal (score)	0(0, 2)	0(0, 0)	0.953
MYOACT pulmonary (score)	6(0, 7)	6(0, 7)	0.033*
MYOACT cardiovascular (score)	0(0, 6)	6(0, 7)	＜0.001***
MYOACT muscle (score)	5(0, 6.5)	5(0, 7)	0.478
MITAX constitutional (score)	3(3, 3)	3(3, 3)	0.994
MITAX cutaneous (score)	3(0, 3)	1(0, 3)	0.027*
MITAX skeletal (score)	0(0, 1)	0(0, 0)	0.183
MITAX gastrointestinal (score)	0(0, 1)	0(0, 1)	0.779
MITAX pulmonary (score)	3(0, 9)	3(0, 9)	0.462
MITAX cardiovascular (score)	0(0, 9)	9(0, 9)	＜0.001***
MITAX muscle (score)	1(0, 3)	1(0, 3)	0.899
MYOACT global (score)	0.35±0.11	0.37±0.12	0.046*
MITAX global (score)	0.27(0.18,0.35)	0.29(0.21,0.40)	0.043*
Clinical manifestation, n/total (%)
Fever	23(19.01)	37(21.64)	0.689
Loss of weight	33(27.27)	60(35.09)	0.199
Fatigue	91(75.21)	131(76.61)	0.891
Chest pain	6(4.96)	16(9.36)	0.239
Palpitation	13(10.74)	36(21.05)	0.031*
Shortness of breath/ dyspnea	70(57.85)	115(67.25)	0.129
Rash	84(69.42)	89(52.05)	0.004**
Weakness in the proximal muscles	59(48.76)	80(46.78)	0.830
Myodynia	43(35.54)	68(39.77)	0.541
Arthritis / arthralgia	49(40.50)	46(26.90)	0.021*
Dysphagia	30(24.79)	42(24.56)	0.926
Cough	59(48.76)	77(45.03)	0.610
Expectoration	53(43.80)	69(40.35)	0.639
Heart rate, beats per minute	91.63±14.31	89.42±15.11	0.209
Respiratory rate, breathes per minute	20.04±0.98	20.56±2.10	0.048*
Clinical diagnosis myocarditis, n(%)	5(4.13)	22(12.87)	0.020*
Treatments for IIMs
Glucocorticoids	50.00(35.00,50.00)	45.00(30.00,50.00)	0.400
Cyclophosphamide	27(22.31)	48(28.07)	0.331
Methotrexate	11(9.09)	18(10.53)	0.837
Mycophenolate mofetil	10(8.26)	14(8.70)	0.931
Ciclosporin A/Tacrolimus	42(34.71)	59(34.50)	0.930
Tofacitinib/Baricitinib	12(9.92)	20(11.70)	0.772
Rituximab	0	3	-
Gamma globulin	11(9.09)	22(12.87)	0.415
Plasmapheresis	0	2	-

*indicates a significant difference between two groups, *p<0.05, **p<0.01, ***p<0.001. ^§The bode-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. ^#The time from improvement of COVID-19 related symptoms and negative throat swab results to admission. Abbreviations: COPD, chronic obstructive pulmonary disease; MYOACT, Myositis Disease Activity Assessment Visual Analog Scales; MITAX, Myositis Intention to Treat Activity Index.

Table 2. Laboratory findings of IIMs patients on admission to the hospital

Characteristic	No prior COVID-19 (NPC, n=121)	Prior COVID-19 (PC, n=171)	p
Myositis specific antibodies (MSA)
MSA, negative, n (%)	21(17.36)	36(21.05)	0.525
MDA5, positive, n (%)	45(37.71)	45(26.44)	0.064
ARS, positive, n (%)	14(11.57)	42(24.56)	0.009**
Mi2/SAE, positive, n (%)	6(4.96)	9(5.26)	0.878
NXP2/TIF1γ, positive, n (%)	16(13.22)	15(8.77)	0.306
SRP/HMGCR, positive, n (%)	21(17.36)	31(18.13)	0.988
ANA, positive, n/total (%)	62/119(52.10)	96/161(59.63)	0.257
+~++, n/total (%)	42/119(35.29)	59/161(36.65)	-
≥3+, n/total (%)	20/119(16.81)	37/161(22.98)	-
Anti-Ro52, positive, n/total (%)	44/119(36.98)	80/161(49.69)	0.046*
MYO (ng/ml)	53.25(21.82, 462.50)	128.50(26.70, 620.25)	0.030*
CK-MB (ng/ml)	3.04(1.18, 21.52)	7.32(1.64, 70.50)	0.015*
cTnT (ng/L)	22.00(9.65, 101.35)	54.50(15.90, 153.00)	0.011*
NT-proBNP (ng/L)	97.50(41.75, 232.50)	133.00(61.50,322.50)	0.028*
CK (IU/L)	113.00(43.50, 1149.50)	250.00(54.00, 1735.00)	0.163
LDH (IU/L)	316.00(234.50, 488.50)	360.00(250.00, 590.00)	0.033*
HBDH (IU/L)	231.00(176.00, 366.00)	274.00(194.00, 429.00)	0.019*
ALT (U/L)	40.00(22.50, 91.50)	48.00(24.00, 99.00)	0.477
AST (U/L)	46.00(25.00, 103.00)	49.00(24.00, 95.00)	0.793
ALP (U/L)	66.00(52.50, 84.50)	73.00(55.00, 91.00)	0.110
GGT (U/L)	28.00(18.00, 60.50)	41.00(19.00, 98.00)	0.048*
Creatinine (umol/L)	51.00(41.00, 62.50)	52.00(43.00, 61.00)	0.754
Triglyceride (mmol/L)	1.95(1.37,2.60)	1.96(1.42,2.79)	0.379
Cholesterol (mmol/L)	4.85(4.00,5.73)	4.81(4.11,5.76)	0.990
AT-III activity (%)	92.57±17.73	90.74±13.45	0.380
FIB (g/L)	3.03(2.40,4.08)	2.67(2.21,3.38)	0.002**
White blood cell count (×10⁹/L)	6.40(4.46, 9.11)	7.44(5.48, 9.75)	0.018*
Neutrophils（%）	70.40(59.95,80.15)	72.20(64.30,80.90)	0.179
Neutrophils count (×10⁹/L)	4.39(2.89, 7.27)	5.30(3.76, 7.18)	0.023*
Lymphocyte (%)	19.50(11.55,25.85)	17.40(10.60,23.30)	0.246
Lymphocyte count (×10⁹/L)	1.06(0.75, 1.63)	1.25(0.80, 1.76)	0.221
Platelet count (×10⁹ /L)	219.00(174.50,261.50)	198.00(157.00,246.00)	0.014*
Hemoglobin (mg/L)	125.72±18.14	127.75±18.33	0.351
CRP (mg/L)	4.68(1.98, 9.82)	4.69(2.38, 11.00)	0.246

*indicates statistical difference between two groups, *P<0.05 **P＜0.01. Abbreviations: MAS, myositis specific antibody; MDA5, antimelanoma differentiation associated gene 5 antibody; ARS, anti-aminoacyl transfer RNA synthetase antibody; NXP2, antinuclear matrix protein 2 antibody; Mi2, anti-helicase protein antibody; SAE, anti-small ubiquitin-like modifier activating enzyme; TIF1γ, anti-transcription intermediary factor 1 γ; HMGCR, anti-3-hydroxy-3-methyglutaryl coenzyme A reductase; SRP, anti-signal recognition particle; ANA, antinuclear antibody; Ro52, anti-cytoplasmic ribonucleoprotein of 52 kDa; MYO, myoglobin; CK-MB, creatinine kinase MB; cTnT, cardiac troponin T; NT-proBNP, N-terminal pro-B-type natriuretic peptide; CK, creatine kinase; LDH, lactate dehydrogenase; HBDH, hydroxybutyrate dehydrogenase; ALT, alanine transaminase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma glutamyltransferase; AT-III, antithrombin III; FIB, fibrinogen; CRP, C-reactive protein;

Table 3. Echocardiographic characteristics of IIMs patients

Characteristic	No prior COVID-19 (NPC, n=111)	Prior COVID-19 (PC, n=149)	p
LV, mm	45.52±3.25	46.43±3.68	0.040*
LA, mm	31(28.00, 34.00)	33.00(30.00, 36.00)	0.013*
RV, mm	21.00(19.00, 22.00)	20.00(19.00, 22.00)	0.845
RA, mm	32.00(29.00,35.00）	32.00(30.00,36.00)	0.062
IVS, mm	9.00(8.00, 10.00)	10.00(9.00, 11.00)	0.043*
LVPW, mm	9.00(8.00, 9.00)	9.00(8.00, 9.00)	0.042*
AAO, mm	31.00(28.00,33.25)	32.00(29.00,34.00)	0.227
MPA, mm	22.00(20.00, 23.00)	22.00(20.00, 23.00)	0.846
E, m/s	0.70(0.60, 0.88)	0.70(0.60, 0.90)	0.922
A, m/s	0.80(0.70,0.90)	0.80(0.70,1.00)	0.477
E/A≤1, n(%)	63(56.76)	98(65.77)	0.176
AV, m/s	1.30(1.20,1.50)	1.30(1.20,1.50)	0.276
PV, m/s	0.90(0.80, 1.00)	0.90(0.80, 1.00)	0.845
e’, cm/s	7.00(5.00, 9.00)	6.00(5.00, 8.00)	0.131
a’, cm/s	8.00(7.00,9.00)	8.00(7.00, 10.00)	0.605
E/ e’	10.00(8.00, 12.00)	11.00(8.00, 13.00)	0.236
E/ e’＜8, n(%)	16(14.55)	10(10.53)	0.514
EDD, mm	45.00(44.00, 48.00)	47.00(44.00, 49.00)	0.057
ESD, mm	29.00(26.00, 30.00)	29.00(26.00, 31.00)	0.199
EDV, ml	94.81±15.76	99.49±18.73	0.036*
ESV, ml	30.00(24.75, 35.00)	31.00(25.00, 39.00)	0.157
SV, ml	63.95±10.91	66.16±11.75	0.124
EF, %	68.00(63.00, 72.00)	68.00(63.00, 73.00)	0.856
FS, %	38.00(34.00,41.00)	38.00(34.00,41.00)	0.940

* indicates a significant difference between two groups, *P<0.05. Abbreviations: LV, left ventricle; LA, left atrium; RV, right ventricle; RA, right atrium; IVS, interventricular septum; LVPW, left-ventricular posterior wall; AAO, ascending aorta. MPA, main pulmonary artery; E, peak velocity of left ventricular early-diastolic fast filling; A, peak velocity of left ventricular late-diastolic filling; AV, aortic valve; PV, pulmonary valve; e’, velocity of early diastolic myocardial movement at mitral ring; a’, velocity of late diastolic myocardial movement at mitral ring; EDD, end-diastolic dimension; ESD, end-systolic dimension; EDV, end-diastolic volume; ESV, end-systolic volume; SV, stroke volume per minute; EF, ejection fraction; FS, fraction shortening;

No competing interests reported.

Investigating the Profile of Patients with Idiopathic Inflammatory Myopathies in the Post-COVID-19 Period: Emphasizing Myocardial Injury

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Version 1

Abstract

Figures

1. Introduction

2. Methods

2.1 Research design and subjects

2.2 Collection of clinical features

2.3 Myositis Disease Activity Assessment

2.4 Analysis of Differentially Expressed Genes

2.5 Statistical analysis

3. Results

3.1 Baseline demographics

3.2 Effects of COVID-19 on the clinical characteristics of patients with IIMs

3.3 Echocardiographic parameters exhibited alterations in IIMs patients with a history of COVID-19

3.4 The putative mechanism underlying COVID-19-induced cardiac damage in patients with IIMs

4. Discussion

5. Conclusions

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1